The Mechanisms of Muscle Hypertrophy Schoenfeld

BRIEF REVIEW
THE MECHANISMS OF MUSCLE HYPERTROPHY AND

THEIR APPLICATION TO RESISTANCE TRAINING
BRAD J. SCHOENFELD
Global Fitness Services, Scarsdale, New York
ABSTRACT
Schoenfeld, BJ. The mechanisms of muscle hypertrophy and
their application to resistance training. J Strength Cond Res
24(10): 28572872, 2010The quest to increase lean body
mass is widely pursued by those who lift weights. Research is
lacking, however, as to the best approach for maximizing
exercise-induced muscle growth. Bodybuilders generally train
with moderate loads and fairly short rest intervals that induce
high amounts of metabolic stress. Powerlifters, on the other
hand, routinely train with high-intensity loads and lengthy rest
periods between sets. Although both groups are known to
display impressive muscularity, it is not clear which method is
superior for hypertrophic gains. It has been shown that many
factors mediate the hypertrophic process and that mechanical
tension, muscle damage, and metabolic stress all can play a role
in exercise-induced muscle growth. Therefore, the purpose of
this paper is twofold: (a) to extensively review the literature as to
the mechanisms of muscle hypertrophy and their application to
exercise training and (b) to draw conclusions from the research
as to the optimal protocol for maximizing muscle growth.
KEY WORDS muscle development, hypertrophic response,

muscle growth, muscle tension, muscle damage, metabolic stress
INTRODUCTION
he quest to increase lean body mass is widely

pursued by those who lift weights. Given the strong
correlation between muscle cross-sectional area
and muscular strength (111), increased muscle
mass is a primary goal of athletes involved in strength and
power sports such as football, rugby, and powerlifting.
Muscle mass also is vital to the sport of bodybuilding, where
competitors are judged on both the quantity and quality of
their muscle development. On a more general level, muscle
hypertrophy is also pursued by the many recreational lifters
who aspire to develop their physiques to the fullest.
Therefore, the maximization of muscle mass has far reaching
Address correspondence to Brad Schoenfeld, brad@workout911.com.

24(10)/28572872
Journal of Strength and Conditioning Research
2010 National Strength and Conditioning Association
implications to a variety of populations associated with sports

and health.
In untrained subjects, muscle hypertrophy is virtually
nonexistent during the initial stages of resistance training,
with the majority of strength gains resulting from neural
adaptations (124). Within a couple of months of training,
however, hypertrophy begins to become the dominant
factor, with the upper extremities shown to hypertrophy
before the lower extremities (124,177). Genetic background,
age, gender, and other factors have been shown to mediate
the hypertrophic response to a training protocol, affecting
both the rate and the total amount of gains in lean muscle
mass (93). Further, it becomes progressively more difficult to
increase lean muscle mass as one gains training experience,
heightening the importance of proper routine design.
Although muscle hypertrophy can be attained through
a wide range of resistance training programs, the principle of
specificity dictates that some routines will promote greater
hypertrophy than others (16). Research is lacking, however,
as to the best approach for achieving this goal. Bodybuilders
generally train with moderate loads and fairly short rest
intervals that induce high amounts of metabolic stress.
Powerlifters, on the other hand, routinely train with highintensity loads and lengthy rest periods between sets.
Although both groups are known to display impressive muscularity, it is not clear which method is best for maximizing
hypertrophic gains (149) or whether other training methods
may perhaps be superior. Therefore, the purpose of this
paper is twofold: (a) to extensively review the literature as to
the mechanisms of muscle hypertrophy and their application
to resistance training variables and (b) to draw conclusions
from the research and develop a hypertrophy-specific routine
for maximizing muscle growth.
TYPES OF MUSCLE HYPERTROPHY

Muscle hypertrophy can be considered distinct and separate
from muscle hyperplasia. During hypertrophy, contractile
elements enlarge and the extracellular matrix expands to
support growth (187). This is in contrast to hyperplasia,
which results in an increase in the number of fibers within
a muscle. Contractile hypertrophy can occur either by adding
sarcomeres in series or in parallel.
The majority of exercise-induced hypertrophy subsequent
to traditional resistance training programs results from an
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Mechanisms of Muscle Hypertrophy

increase of sarcomeres and myofibrils added in parallel
(135,179). When skeletal muscle is subjected to an overload
stimulus, it causes perturbations in myofibers and the related
extracellular matrix. This sets off a chain of myogenic events
that ultimately leads to an increase in the size and amounts
of the myofibrillar contractile proteins actin and myosin,
and the total number of sarcomeres in parallel. This, in turn,
augments the diameter of individual fibers and thereby results
in an increase in muscle cross-sectional area (182).
A serial increase in sarcomeres results in a given muscle
length corresponding to a shorter sarcomere length (182). Inseries hypertrophy has been shown to occur when muscle is
forced to adapt to a new functional length. This is seen with
limbs that are placed in a cast, where immobilization of
a joint at long muscle lengths results in an increased number
of sarcomeres in series, whereas immobilization at shorter
lengths causes a reduction (182). There is some evidence that
certain types of exercise can affect the number of sarcomeres
in series. Lynn and Morgan (107) showed that when rats
climbed on a treadmill (i.e., incline), they had a lower
sarcomere count in series than those who descended (i.e.,
decline). This suggests that repeated eccentric-only actions
lead to a greater number of sarcomeres in series, whereas
exercise consisting solely of concentric contractions results in
a serial decrease in sarcomere length.
It is hypothesized that hypertrophy may be augmented
by an increase in various noncontractile elements and fluid
(108,205). This has been termed sarcoplasmic hypertrophy, and may result in greater muscle bulk without
concomitant increases in strength (154). Increases in
sarcoplasmic hypertrophy are thought to be training specific,
a belief perpetuated by studies showing that muscle
hypertrophy is different in bodybuilders than in powerlifters
(179). Specifically, bodybuilders tend to display a greater
proliferation of fibrous endomysial connective tissue and
a greater glycogen content compared to powerlifters
(109,177), presumably because of differences in training
methodology. Although sarcoplasmic hypertrophy is often
described as nonfunctional, it is plausible that chronic
adaptations associated with its effects on cell swelling may
mediate subsequent increases in protein synthesis that lead
to greater contractile growth.
Some researchers have put forth the possibility that
increases in cross-sectional area may be at least partly
because of an increase in fiber number (8). A meta-analysis by
Kelley (84) found that hyperplasia occurs in certain animal
species under experimental conditions as a result of
mechanical overload. Increases in muscle fiber number were
greatest among those groups that used an avian vs.
a mammalian model, and stretch overload yielded larger
increases in fiber count than exercise. However, subsequent
research suggests that such observations may be erroneous,
with results attributed to a miscounting of the intricate
arrangements of elongating fibers as a greater fiber number
(135). Evidence that hyperplasia occurs in human subjects is
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lacking and, if it does occur at all, the overall effects on muscle

cross-sectional area would appear to be minimal (1,108).
SATELLITE CELLS AND MUSCLE HYPERTROPHY

Muscle is a postmitotic tissue, meaning that it does not
undergo significant cell replacement throughout life. An
efficient method for cell repair is therefore required to avoid
apoptosis and maintain skeletal mass. This is carried out
through the dynamic balance between muscle protein
synthesis and degradation (69,182). Muscle hypertrophy
occurs when protein synthesis exceeds protein breakdown.
Hypertrophy is thought to be mediated by the activity
of satellite cells, which reside between the basal lamina
and sarcolemma (66,146). These myogenic stem cells are
normally quiescent but become active when a sufficient
mechanical stimulus is imposed on skeletal muscle (187).
Once aroused, satellite cells proliferate and ultimately fuse to
existing cells or among themselves to create new myofibers,
providing the precursors needed for repair and subsequent
growth of new muscle tissue (182).
Satellite cells are thought to facilitate muscle hypertrophy
in several ways. For one, they donate extra nuclei to muscle
fibers, increasing the capacity to synthesize new contractile
proteins (123). Because a muscles nuclear-content-to-fibermass ratio remains constant during hypertrophy, changes
require an external source of mitotically active cells. Satellite
cells retain mitotic capability and thus serve as the pool of
a myonuclei to support muscle growth (15). This is consistent
with the concept of myonuclear domain, which proposes
that the myonucleus regulates mRNA production for a finite
sarcoplasmic volume and any increases in fiber size must be
accompanied by a proportional increase in myonuclei. Given
that muscles are comprised of multiple myonuclear domains,
hypertrophy could conceivably occur as a result of either
an increase in the number of domains (via an increase in
myonuclear number) or an increase in the size of existing
domains. Both are thought to occur in hypertrophy, with
a significant contribution from satellite cells (182).
Moreover, satellite cells coexpress various myogenic
regulatory factors (including Myf5, MyoD, myogenin, and
MRF4) that aid in muscle repair, regeneration, and growth
(27). These regulatory factors bind to sequence specific DNA
elements present in the muscle gene promoter, with each
playing distinct roles in myogenesis (148,155).
MYOGENIC PATHWAYS
Exercise-induced muscle hypertrophy is facilitated by
a number of signaling pathways, whereby the effects of
mechano-stimulation are molecularly transduced to downstream targets that shift muscle protein balance to favor
synthesis over degradation. Several primary anabolic signaling pathways have been identified including Akt/mammalian
target of rapamycin (mTOR), mitogen-activated protein
kinase (MAPK), and calcium-(Ca2+) dependent pathways.
The following is an overview of each of these pathways.
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Akt/Mammalian Target of Rapamycin Pathway
The Akt/mTOR pathway is believed to act as a master

network regulating skeletal muscle growth (18,77,181).
Although the specific molecular mechanisms have not been
fully elucidated, Akt is considered a molecular upstream
nodal point that is both an effector of anabolic signaling and
a dominant inhibitor of catabolic signals (126,182). When
activated, Akt signals mTOR, which then exerts effects on
various downstream targets that promote hypertrophy in
muscle tissue.
Mitogen-Activated Protein-Kinase Pathway
Mitogen-activated protein kinase is considered a master

regulator of gene expression, redox status, and metabolism
(88). Specific to exercise-induced skeletal muscle hypertrophy, MAPK has been shown to link cellular stress with an
adaptive response in myocytes, modulating growth and
differentiation (147). Three distinct MAPK signaling modules
are associated with exercise-induced muscle hypertrophy:
extracellular signal-regulated kinases (ERK 1/2), p38 MAPK,
and c-Jun NH2terminal kinase (JNK). Of these modules,
JNK has shown to be the most responsive to mechanical
tension and muscle damage, and it is particularly sensitive to
eccentric exercise. Exercise-induced activation of JNK has
been linked to a rapid rise in mRNA of transcription factors
that modulate cell proliferation and DNA repair (9,10).
Calcium-Dependent Pathways
Various Ca2+-dependent pathways have been implicated in

the regulation of muscle hypertrophy. Calcineurin (Cn), a
Ca2+-regulated phosphatase, is believed to be a particularly
critical regulator in the Ca2+ signaling cascade. Cn acts downstream in the Ca2+ pathway and mediates various hypertrophic effectors such as myocyte enhancing factor 2, GATA
transcription factors, and nuclear factor of activated T cells
(118). Cn-dependent signaling is linked to hypertrophy of all
fiber types, and its inhibition has been shown to prevent
muscle growth even in the presence of muscular overload
(35,36).
HORMONES AND CYTOKINES

Hormones and cytokines play an integral role in the hypertrophic response, serving as upstream regulators of anabolic
processes. Elevated anabolic hormone concentrations increase the likelihood of receptor interactions, facilitating
protein metabolism and subsequent muscle growth (31).
Many are also involved in satellite cell proliferation and
differentiation and perhaps facilitate the binding of satellite
cells to damaged fibers to aid in muscular repair (182,187).
The hormonal regulation of hypertrophy is complex, with
many hormones and cytokines believed to contribute to the
response. Hepato growth factor, Interleukin-5 (IL-5), Interleukin-6 (IL-6), fibroblast growth factor, and leukemia
inhibitory factor, all have been shown to promote anabolism
(162,182,187). Insulin also has been shown to possess
anabolic properties, with greater effects on attenuating
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proteolysis rather than heightening protein synthesis. Insulin

also is believed to induce mitosis and differentiation of
satellite cells (187). Given that insulin levels are suppressed
during exercise, however, it is not a modifiable aspect of an
exercise regimen and thus will not be addressed further here.
Various types of exercise have been shown to cause acute,
and in some cases chronic, hormonal alterations that appear
to play a role in mediating hypertrophic signaling systems
(119). The 3 most widely studied of these hormones are
insulin-like growth factor (IGF-1), testosterone, and growth
hormone (GH). Whether the acute hormonal response to
exercise provides a significant anabolic stimulus has been
questioned by some researchers (191,194), however with
the inherent experimental limitations in these studies and a
larger body of prevailing basic and applied evidence to
the contrary, such an overt dismissal of the importance of
hormonal signaling in the physiological adaptations resulting
from resistance exercise over a training period is without
context and premature.
Insulin-Like Growth Factor
Insulin-like growth factor is often referred to as the most

important mammalian anabolic hormone. It is thought to
provide the main anabolic response for the body as a whole
and shows enhanced effects in response to mechanical
loading (19,63). Structurally, IGF-1 is a peptide hormone, so
named because of its structural similarities to insulin. Insulinlike growth factor receptors are found in activated satellite
cells, adult myofibers, and Schwann cells (15). During
exercise, muscles not only produce more systemic IGF-1
than the liver but also use more circulating IGF-1 (49).
Availability of IGF-1 for muscle is controlled by IGF-1
binding proteins (IGFBPs), which either stimulate or inhibit
the effects of IGF-1 after binding to a specific IGFBP (182).
Three distinct IGF-1 isoforms have been identified: the
systemic forms IGF-1Ea and IGF-1Eb, and a splice variant, IGF1Ec. Although all 3 isoforms are expressed in muscle tissue, only
IGF-1Ec appears to be activated by mechanical signals (63,199).
Because of its response to mechanical stimulation, IGF-1Ec is
familiarly called mechano growth factor (MGF).
Although the exact mechanisms of IGF-1s mode of action
have not been fully elucidated, it is believed that mechanostimulation causes the IGF-1 gene to be spliced toward MGF,
which in turn kick starts muscle hypertrophy. Within a day
or so, MGF then completely splices toward the systemic
IGF-1 isoforms (IGF-1Ea and IGF-1Eb) (54,69). Levels of
IGF-1 then remain elevated in muscle tissue for some time
thereafter, with myogenic effects seen up to 72 hours
postexercise (117). Although MGF has been shown to be
particularly sensitive to muscle damage, it is not clear
whether the isoform is upregulated by membrane damage or
if membrane damage initiates MGF production (48).
Insulin-like growth factor has been shown to induce
hypertrophy in both an autocrine and paracrine manner (34)
and exerts its effects in multiple ways. For one, IGF-1 directly
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promotes anabolism by increasing the rate of protein
synthesis in differentiated myofibers (15,63). Moreover,
locally expressed MGF has been shown to activate satellite
cells and mediate their proliferation and differentiation
(69,200). IGF-IEa, on the other hand, is thought to enhance
fusion of satellite cells with muscle fibers, facilitating the
donation of myonuclei and helping to maintain optimal DNA
to protein ratios in muscle tissue (182).
Insulin-like growth factor also activates L-type calcium
channel gene expression, resulting in an increased intracellular Ca2+ concentration (125). This leads to the activation
of multiple anabolic Ca2+-dependent pathways, including
calcineurin and its numerous downstream signaling targets.
correlations between training-induced elevations in testosterone

and muscle cross-sectional area, suggesting that acute, exerciseinduced elevations in testosterone may play an important role
in muscle hypertrophy. However, acute responses are limited in
women and the elderly, mitigating the hypertrophic potential in
these populations (61,90,130).
The chronic effects of resistance training on bodily
testosterone concentrations are not clear at this time.
Although some studies show sustained increases as a result
of regimented resistance exercise (60,93,163), others show
little to no change (3,142). Further research is needed to
enhance understanding on this topic.
Growth Hormone
Testosterone
Testosterone is a cholesterol-derived hormone that has a

considerable anabolic effect on muscle tissue (33,105). In
addition to its effects on muscle, testosterone also can interact
with receptors on neurons and thereby increase the amount
of neurotransmitters released, regenerate nerves, and increase
cell body size.
The majority of testosterone is synthesized and secreted by
the Leydig cells of the testes via the hypothalamicpituitary
gonadal axis, with small amounts derived from the ovaries and
adrenals (22). In the blood, the great majority of testosterone
is bound to either albumin (38%) or steroid hormone binding
globulin (60%), with the remaining 2% circulating in an
unbound state. Although only the unbound form is biologically active and available for use by tissues, weakly
bound testosterone can become active by rapidly disassociating from albumin (105). Unbound testosterone binds to
androgen receptors of target tissues, which are located in the
cells cytoplasm. This causes a conformational change that
transports the testosterone to the cell nucleus where it
interacts directly with chromosomal DNA.
Although the effects of testosterone on muscle are seen in the
absence of exercise, its actions are magnified by mechanical
loading, promoting anabolism both by increasing the protein
synthetic rate and inhibiting protein breakdown (22). Testosterone may also contribute to protein accretion indirectly by
stimulating the release of other anabolic hormones such as
GH (31). Moreover, it has been shown to promote satellite cell
replication and activation, resulting in an increase in the
number of myogenically committed satellite cells (155).
Suppression of testosterone has been shown to seriously
compromise the response to resistance exercise (100).
Resistance training also has been shown to upregulate
androgen receptor content in humans (13,80). In rodents,
modulation of androgen receptor content appears to take
place in a fiber-type specific manner, with increases specific
to fast-twitch muscles (20). This would seem to enhance the
potential for testosterone binding at the cellular level, and
thus facilitate its uptake into target tissues.
Resistance exercise can have a substantial acute effect
on testosterone secretion. Ahtiainen et al. (2) found significant
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Growth hormone is a polypeptide hormone considered to

have both anabolic and catabolic properties. Specifically, GH
acts as a repartitioning agent to induce fat metabolism toward
mobilization of triglycerides, and stimulating cellular uptake
and incorporation of amino acids into various proteins,
including muscle (187). In the absence of mechanical loading,
GH preferentially upregulates the mRNA of systemic IGF-1,
and mediating nonhepatic IGF-1 gene expression in an
autocrine/paracrine manner (63).
Growth hormone is secreted by the anterior pituitary gland
and released in a pulsatile fashion, with the greatest
nonexercise secretions occurring during sleep. More than
100 molecular isoforms of GH have been identified; however,
most resistance training studies have focused solely on the
22-kDa isoform, limiting conclusions. Recent research
suggests a preferential release of multiple GH isoforms with
extended half-lives during exercise, allowing for sustained
action on target tissues (131).
In addition to exerting effects on muscle tissue, GH also is
involved in the regulation of immune function, bone modeling, and extracellular fluid volume. In total, GH is implicated
as promoting over 450 actions in 84 cell types (190).
Growth hormone levels spike after the performance of
various types of exercise (96). An exercise-induced increase in
GH has been highly correlated with the magnitude of type I
and type II muscle fiber hypertrophy (113). It is postulated
that a transient GH increase may lead to an enhanced
interaction with muscle cell receptors, facilitating fiber
recovery and stimulating a hypertrophic response (134).
Growth hormone is also thought to be involved in the
training-induced increase of locally expressed IGF-1 (75).
When combined with intense exercise, GH release is
associated with marked upregulation of the IGF-1 gene in
muscle so that more is spliced toward the MGF isoform (63).
Some researchers have questioned whether GH does, in
fact, have a significant hypertrophic effect on muscle tissue
(143). This view is based on the results of several studies that
have failed to find significant increases in muscle mass when
GH was administered as part of a resistance training protocol
(101,201203). However, these protocols did not replicate
the large spikes in GH seen postexercise, nor did they take
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into account the time course of GH elevation in conjunction
with myotrauma. Thus, it is impossible to draw conclusions
from these studies as to whether an exercise-induced GH
response is associated with skeletal muscle anabolism. Much
is still unclear about the anabolic actions of GH, and further
research is needed to fully elucidate its role in muscular
development.
CELL SWELLING
Cellular hydration (i.e., cell swelling) serves as a physiological
regulator of cell function (65). It is known to simulate anabolic
processes, both through increases in protein synthesis and
decreases in proteolysis (53,120,165). Although a physiological
basis linking cell swelling with an anabolic drive is yet to be
determined, it is conceivable that increased pressure against
the membrane is perceived as a threat to cellular integrity,
which in turn causes the cell to initiate a signaling response
that ultimately leads to reinforcement of its ultrastructure.
A hydrated cell has been shown to initiate a process that
involves activation of protein-kinase signaling pathways in
muscle, and possibly mediating autocrine effects of growth
factors in signaling the anabolic response to membrane stretch
(106). Cell swelling induced membrane stretch may also have
a direct effect on the amino acid transport systems mediated
through an integrin-associated volume sensor. Phosphatidylinositol 3-kinase appears to be an important signaling component
in modulating glutamine and alpha-(methyl)aminoisobutyric
acid transport in muscle because of cell swelling (106).
Resistance exercise has been shown to induce alterations of
intra- and extracellular water balance (156), the extent of
which is dependent upon the type of exercise and intensity
of training. Cell swelling is maximized by exercise that relies
heavily on glycolysis, with the resultant lactate accumulation
acting as the primary contributor to osmotic changes in
skeletal muscle (41,157). Fast-twitch fibers are particularly
sensitive to osmotic changes, presumably related to a high
concentration of water transport channels called aquaporin-4.
Aquaporin-4 has been shown to be strongly expressed in the
sarcolemma of mammalian fast-twitch glycolytic and fasttwitch oxidative-glycolytic fibers, facilitating the influx
of fluid into the cell. Given that fast-twitch fibers are most
responsive to hypertrophy, it is conceivable that cellular
hydration augments the hypertrophic response during
resistance training that relies heavily on anaerobic glycolysis.
Exercise regimens that cause an increased glycogen storage
capacity also have the potential to augment cell swelling.
Given that glycogen attracts three grams of water for every
gram of glycogen (25), this may reflect an increased capacity
for protein synthesis in those who possess greater intramuscular glycogen stores.
HYPOXIA
Hypoxia has been shown to contribute to increases in muscle
hypertrophy, with effects seen even in the absence of exercise.
Takarada et al. (172) found that 2 daily sessions of vascular
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occlusion significantly attenuated muscular atrophy in

a group of patients confined to bed rest. Similar findings
were observed by Kubota et al. (62,98), with occlusion
conferring a protective effect on muscle strength and crosssectional area during a 2-week period of leg immobilization.
When combined with exercise, hypoxia seems to have an
additive effect on hypertrophy. This was demonstrated by
Takarada et al. (173), who divided 24 older women into
3 subgroups: low-intensity elbow flexion exercise (;50%
1 repetition maimum [1RM]) with vascular occlusion, lowintensity elbow flexion exercise (;50% 1RM) without occlusion, and high- to medium-intensity elbow flexion exercise
without occlusion (;80% 1RM). After 16 weeks, the group
that performed low-intensity training with occlusion showed
a significantly greater cross-sectional area of the elbow flexor
muscles as compared to low-intensity exercise without occlusion. Moreover, the hypertrophic gains realized were similar
to those experienced by the moderate- to high-intensity group.
There are several theories as to the potential hypertrophic
benefits of muscle hypoxia. For one, hypoxia has been shown
to cause an increased lactate accumulation and reduced acute
lactate clearance rate (173). This may mediate increased cell
swelling, which has been shown to upregulate protein synthesis. Moreover, the rise in lactate may mediate elevations in
anabolic hormones and cytokines. Takarada et al. (172) noted
a 290% increase in GH levels after low-intensity hypoxic
training and an increase in the concentration of the myogenic
cytokine IL-6, which was sustained for 24 hours postexercise.
Another potential mechanism of hypoxic-induced hypertrophy is its effect on the activity of reactive oxygen species
(ROS). Reactive oxygen species production has been shown
to promote growth in both smooth muscle and cardiac
muscle (170), and it is theorized to have similar hypertrophic
effects on skeletal muscle (171). Nitric oxide, an ROS produced during exercise, has been shown to mediate the proliferation of satellite cells, which would presumably lead to
greater skeletal muscle growth (81,174). Reactive oxygen
species generated during resistance training also has been
shown to activate MAPK signaling in skeletal myoblasts (83),
potentially modulating a hypertrophic response.
Hypoxia also may promote hypertrophic effects from
reactive hyperemia (i.e., increased blood flow) after ischemic
exercise (173). Hyperemia within damaged muscle would
conceivably allow for the delivery of anabolic endocrine
agents and growth factors to satellite cells, thereby regulating
their proliferation and subsequent fusion into myotubes (187).
INITIATION OF EXERCISE-INDUCED MUSCLE

HYPERTROPHY
It is hypothesized that 3 primary factors are responsible for
initiating the hypertrophic response to resistance exercise:
mechanical tension, muscle damage, and metabolic stress
(38,79,153,185). The following is an overview of each of these
factors.
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Mechanical Tension
Mechanically induced tension produced both by force generation and stretch is considered essential to muscle growth, and
the combination of these stimuli appears to have a pronounced additive effect (48,72,185). More specifically, mechanical overload increases muscle mass while unloading results
in atrophy (47). This process appears largely controlled by
protein synthetic rate during the initiation of translation (11,87).
It is believed that tension associated with resistance training
disturbs the integrity of skeletal muscle, causing mechanochemically transduced molecular and cellular responses
in myofibers and satellite cells (182). Upstream signaling is
thought to occur through a cascade of events that involve
growth factors, cytokines, stretch-activated channels, and
focal adhesion complexes (23,48,162). Evidence suggests that
the downstream process is regulated via the AKT/mTOR
pathway, either through direct interaction or by modulating
production of phosphatidic acid (72,73). At this point,
however, research has not provided a clear understanding of
how these processes are carried out.
During eccentric contractions, passive muscular tension
develops because of lengthening of extramyofibrillar elements, especially collagen content in extracellular matrix and
titin (182). This augments the active tension developed by the
contractile elements, enhancing the hypertrophic response.
Both the amplitude and duration of excitation coupling is
determined by motor unit (MU) firing frequency, the extent
of which are believed to encode signals to various
downstream pathways including Ca2+ calmodulin phosphatase calcineurin, CaMKII, and CAMKIV, and PKC (26).
These pathways help to determine gene expression, coupling
muscle excitation with transcription (182).
Passive tension produces a hypertrophic response that
is fiber-type specific, with an effect seen in fast-twitch but
not slow-twitch fibers. This was demonstrated by Prado et al.
(139), who found that slow-twitch fibers in rabbits exhibited
low passive tension in titin, but the tension was highly
variable in fast-twitch fibers.
Although mechanical tension alone can produce muscle
hypertrophy, it is unlikely to be solely responsible for
hypertrophic gains associated with exercise (79). In fact,
certain resistance training routines employing high degrees of
muscle tension have been shown to largely induce neural
adaptations without resultant hypertrophy (28,188).
Muscle Damage
Exercise training can result in localized damage to muscle

tissue which, under certain conditions, is theorized to
generate a hypertrophic response (38,69). Damage can be
specific to just a few macromolecules of tissue or result in
large tears in the sarcolemma, basal lamina, and supportive
connective tissue, and induces injury to contractile elements
and the cytoskeleton (187). Because the weakest sarcomeres
are located at different regions of each myofibril, the
nonuniform lengthening causes a shearing of myofibrils.
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This deforms membranes, particularly T-tubules, leading to

a disruption of calcium homeostasis and consequently
damage because of tearing of membranes and/or opening
of stretch-activated channels (4).
The response to myotrauma has been likened to the acute
inflammatory response to infection. Once damage is perceived
by the body, neutrophils migrate to the area of microtrauma
and agents are then released by damaged fibers that attract
macrophages and lymphocytes. Macrophages remove cellular
debris to help maintain the fibers ultrastructure and produce
cytokines that activate myoblasts, macrophages and lymphocytes. This is believed to lead to the release of various growth
factors that regulate satellite cell proliferation and differentiation (182,187).
Furthermore, the area under the myoneural junction
contains a high concentration of satellite cells, which have
been shown to mediate muscle growth (69,155). This gives
credence to the possibility that nerves impinging on damaged
fibers might stimulate satellite cell activity, thereby promoting hypertrophy (187).
Metabolic Stress
Numerous studies support an anabolic role of exerciseinduced metabolic stress (145,149,161) and some have
speculated that metabolite accumulation may be more
important than high force development in optimizing the
hypertrophic response to training (153). Although metabolic
stress does not seem to be an essential component of muscular growth (40), a large body of evidence shows that it can
have a significant hypertrophic effect, either in a primary or
secondary manner. This can be noted empirically by examining the moderate intensity training regimes adopted by
many bodybuilders, which are intended to heighten metabolic stress while maintaining significant muscular tension.
Metabolic stress manifests as a result of exercise that relies
on anaerobic glycolysis for ATP production, which results in
the subsequent buildup of metabolites such as lactate,
hydrogen ion, inorganic phosphate, creatine, and others
(169,178). Muscle ischemia also has been shown to produce
substantial metabolic stress, and potentially produces an
additive hypertrophic effect when combined with glycolytic
training (136,182). The stress-induced mechanisms theorized
to mediate the hypertophic response include alterations in
hormonal milieu, cell swelling, free-radical production, and
increased activity of growth-oriented transcription factors
(50,51,171). It also has been hypothesized that a greater acidic
environment promoted by glycolytic training may lead
to increased fiber degradation and greater stimulation of
sympathetic nerve activity, thereby mediating an increased
adaptive hypertrophic response (22).
TRAINING VARIABLES AND MUSCLE HYPERTROPHY

Consistent with the principle of specificity, proper manipulation of training variables is essential for maximizing
exercise-induced muscle hypertrophy. The following is
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a review as to how each training variable impacts the
hypertrophic response with respect to the physiological
variables previously discussed.
Intensity
Intensity (i.e., load) has been shown to have a significant

impact on muscle hypertrophy and is arguably the most
important exercise variable for stimulating muscle growth
(42). Intensity is customarily expressed as a percentage of
1RM and equates to the number of repetitions that can be
performed with a given weight. Repetitions can be classified
into 3 basic ranges: low (15), moderate (612), and high
(15+). Each of these repetition ranges will involve the use of
different energy systems and tax the neuromuscular system in
different ways, impacting the extent of the hypertrophic
response.
The use of high repetitions has generally proven to be
inferior to moderate and lower repetition ranges in eliciting
increases in muscle hypertrophy (24,71). In the absence of
artificially induced ischemia (i.e., occlusion training), a load
less than approximately 65% of 1RM is not considered sufficient to promote substantial hypertrophy (115). Although
such high rep training can bring about significant metabolic
stress, the load is inadequate to recruit and fatigue the highest
threshold MUs.
Whether low reps or moderate reps evoke a greater
hypertrophic response has been a matter of debate, and both
produce significant gains in muscle growth (24). However,
there is a prevailing belief that a moderate range of approximately 612 reps optimizes the hypertrophic response
(86,89,205).
The anabolic superiority of moderate repetitions has been
attributed to factors associated with metabolic stress. Although
low repetition sets are carried out almost exclusively by the
phosphocreatine system, moderate repetition schemes rely
heavily on anaerobic glycolysis (144). This results in
a significant buildup of metabolites. Studies of bodybuildingstyle exercise routines performed with multiple sets of 612
reps show significant postexercise declines in ATP, creatine
phosphate, and glycogen, along with marked increases in
blood lactate, intramuscular lactate, glucose and glucose6-phosphate (37,178). Buildup of these metabolites has been
shown to have a significant impact on anabolic processes (96).
It is therefore conceivable that there is a maximum threshold
for tension-induced hypertrophy, above which metabolic
factors become more important than additional increases
in load.
Resultant to metabolic buildup, moderate repetition range
training has been shown to maximize the acute anabolic
hormonal response of exercise. Both testosterone and GH are
acutely elevated to a greater degree from routines employing
moderate rep sets as compared to those using lower
repetitions (57,90,92,94,114), thereby increasing the potential
for downstream cellular interactions that facilitate remodeling of muscle tissue.
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Training in a moderate repetition range also maximizes

acute cellular hydration. During moderate rep training, the
veins taking blood out of working muscles are compressed
while arteries continue to deliver blood into the working
muscles, thereby creating an increased concentration of
intramuscular blood plasma. This causes plasma to seep out of
the capillaries and into the interstitial spaces. The buildup
of fluid in the interstitial spaces causes an extracellular
pressure gradient, which causes a flow of plasma back into the
muscle causing the phenomenon commonly referred to as
a pump. This is augmented by the accumulation of
metabolic byproducts, which function as osmolytes, drawing
fluid into the cell (157). Whether acute exercise-induced cell
swelling mediates muscle hypertrophy is not known, but it
seems plausible given the known role of hydration in
regulating cell function.
Moreover, the extra time under tension associated with
a moderate repetition scheme as compared to a lower rep
scheme would theoretically enhance the potential for
microtrauma and fatigueability across the full spectrum of
muscle fibers. This would seem to have greatest applicability
for hypertrophy of slow-twitch fibers, which have greater
endurance capacity than fast-twitch fibers and thus would
benefit by increased time under tension. Although slowtwitch fibers are not as responsive to growth as fast-twitch
fibers, they nevertheless do display hypertrophy when subjected to an overload stimulus. Given that the majority of
whole muscles exhibit significant slow-twitch profiles (55,102),
this can potentially help to maximize whole muscle girth.
Some researchers have postulated that muscles containing
a greater percentage of slow-twitch fibers might have the
greatest hypertrophic response to a higher repetition range,
whereas fast-twitch muscles would respond best to lower
repetitions (138,192). Although this concept is intriguing,
a fiber-type prescription with respect to repetition range
has not been borne out by research. Moreover, given the
variability of fiber-type composition between individuals, it
would be difficult to impossible to determine fiber-type ratios
without muscle biopsy, thus making application impractical
for the vast majority of people.
Volume
A set can be defined as the number of repetitions performed

consecutively without rest, whereas exercise volume can be
defined as the product of total repetitions, sets, and load
performed in a training session. Higher-volume, multiple-set
protocols have consistently proven superior over single set
protocols with respect to increased muscle hypertrophy
(97,197).
It is not clear whether the hypertrophic superiority of
higher-volume workloads is the product of greater total
muscle tension, muscle damage, metabolic stress, or some
combination of these factors. Higher-volume, body-buildingstyle programs that generate significant glycolytic activity
have been consistently proven to elevate acute testosterone
2863

levels to a greater extent than low-volume routines (92,94).
Schwab et al. (150) showed that testosterone did not significantly
increase during squat performance until after completion of
the fourth set, indicating a clear benefit of multiple-set routines in
this regard.
Higher-volume programs also have been shown to mediate
the acute release of GH, particularly in routines designed
to heighten metabolic stress (70). A large body of research
shows multiple-set protocols elicit greater GH responses
than single set protocols (29,124). Smilios et al. (158)
compared the GH response of a maximum strength (MS)
routine consisting of 5 reps at 88% of 1RM, 3 minutes rest
with a maximal hypertrophy (MH) routine consisting of 10
reps at 75% of 1RM, 2 minutes rest in young men. Postexercise GH was measured after 2, 4, and 6 sets. GH levels
were significantly greater after the 4-set compared to the
2-set sessions in MH but not in MS, indicating a superiority
of higher-volume routines that generate metabolite buildup.
A split body routine where multiple exercises are performed for a specific muscle group in a session may help to
maximize the hypertrophic response (86). Compared to full
body routines, a split routine allows total weekly training
volume to be maintained with fewer sets performed per
training session and greater recovery afforded between sessions (85). This may enable the use of heavier daily training
loads and thus generate greater muscular tension. Moreover,
split routines can serve to increase muscular metabolic stress
by prolonging the training stimulus within a given muscle
group, potentially heightening acute anabolic hormonal
secretions, cell swelling, and muscle ischemia.
To maximize hypertrophy, evidence exists that volume
should be progressively increased over a given periodized
cycle, culminating in a brief period of overreaching. Overreaching can be defined as a planned, short-term increase in
volume and/or intensity intended to improve performance.
Improvements are thought to be obtained by initiating
a rebound effect where an initial decrease in anabolic drive
causes the body to supercompensate by significantly increasing accretion of body proteins (42,189). Training status
has been shown to affect the overreaching response, with
reduced detrimental effects to the endocrine system seen in
those with 1-plus years of experience (44). To ensure optimal
supercompensation, the period of overreaching should be
followed by a brief taper or cessation from training (99).
Prolonged periods of overreaching, however, can rapidly
lead to an overtrained state (62). Overtraining has catabolic
effects on muscle tissue, and is characterized by chronically
decreased concentrations of testosterone and luteinizing
hormone, and increased cortisol levels (43,58,140). The
cytokine hypothesis of overtraining states that primary cause
of overtraining syndrome is repetitive trauma to the
musculoskeletal system resulting from high-intensity and
high-volume training (159,160). However, studies seem to
show that overtraining is more a result of excessive volume
than intensity (43,59). Given that recuperative abilities are
2864
the
highly variable between individuals, it is essential to be

cognizant of an athletes training status and adjust volume
accordingly to avoid a negative effect on protein accretion.
Furthermore, the quest to train with a high volume must be
balanced with performance decrements arising from lengthy
exercise sessions. Long workouts tend to be associated with
reduced intensity of effort, decreased motivation, and alterations in immune response (92). Accordingly, it has been
proposed that intense workouts should not last longer than
one hour to ensure maximal training capacity throughout the
session (205).
Exercise Selection
It is a well-accepted fitness tenet that varying exercise

parameters (i.e., angle of pull, position of extremities, etc.) can
cause different activation patterns within muscle compartments, and making synergists more active or less active (17).
This is particularly important in a hypertrophy-oriented
protocol, where promoting uniform growth of muscle tissue
is essential for maximizing overall muscle girth.
Muscles can have different attachment sites that provide
greater leverage for varying actions. The trapezius, for
example, is subdivided so that the upper aspect elevates the
scapula, the middle aspect abducts the scapula and the lower
portion depresses the scapula (103). With respect to the
pectoralis major, the sternal head is significantly more active
than the clavicular head in the decline bench press (46).
Further, the clavicular head of the pectoralis major and long
head of the triceps have been shown to be more active in the
narrow grip bench press vs. the wide grip variation, with
anterior deltoid activity increasing in conjunction with
increases in the degree of trunk inclination (14).
Regional differences within various muscles can impact
their response to exercise choice. For example, slow and fast
MUs are often scattered across muscle, so that a slow-twitch
fiber can be activated while an adjacent fast-twitch fiber is
inactive and vice versa (7). Moreover, muscles are sometimes
divided into neuromuscular componentsdistinct regions
of muscle each of which is innervated by its own nerve
branchsuggesting that portions of a muscle can be called
into play depending on the activity (7). For example, the
sartorius, gracilis, biceps femoris, and semitendinosus are all
subdivided by one or more fibrous bands or inscriptions, with
each compartment innervated by separate nerve branches
(193,198). Further, the gracilis and sartorius are composed of
relatively short, in series fibers that terminate intrafascicularly, refuting the supposition that muscle fibers always span
the entire origin to insertion (67).
The effects of muscle partitioning on mechanical activity
are seen in the biceps brachii, where both the long and short
heads have architectural compartments that are innervated
by private branches of the primary neurons (151). Studies
investigating muscle activity of the long head of the biceps
brachii show that MUs in the lateral aspect are recruited for
elbow flexion, MUs in the medial aspect are recruited for
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the
TM

supination, and centrally located MUs are recruited for nonlinear combinations of flexion and supination (175,176,184).
Further, the short head appears to be more active in the latter
part of an arm curl (i.e., greater elbow flexion), whereas the
long head is more active in the early phase (21).
These architectural variances of muscle give support for
the need to adopt a multiplanar, multiangled approach to
hypertrophy training using a variety of different exercises.
Moreover, given the need to fully stimulate all fibers within
a muscle, it would seem that a frequent exercise rotation is
warranted to maximize the hypertrophic response.
There is evidence to support the inclusion of both
multijoint and single-joint exercises in a hypertrophy-specific
routine. Multijoint exercises recruit large amounts of muscle
mass to carry out work. This has an impact on the anabolic
hormonal response to training. Specifically, the magnitude
of postexercise hormonal elevations has been shown to be
related to the extent of muscle mass involved, with multijoint
movements producing larger increases in both testosterone
and GH levels compared to single-joint exercises (64,91).
Moreover, multijoint movements tend to require significant
stabilization of the entire body, thereby involving numerous
muscles that otherwise might not be stimulated in the performance of single-joint movements. The squat, for example,
dynamically recruits not only the quadriceps femoris and hip
extensors but also most of the other lower body muscles
including the hip adductors, hip abductors, and triceps surae
(132). In addition, significant isometric activity is required by
a wide range of supporting muscles (including the abdominals, erector spinae, trapezius, rhomboids, and many others)
to facilitate postural stabilization of the trunk. In all, it is
estimated that over 200 muscles are activated during squat
performance (167). To achieve a comparable degree of muscular coverage would necessitate the performance of dozens
of single-joint movementsa strategy that is both inefficient
and impractical.
On the other hand, single-joint exercises allow for a greater
focus on individual muscles compared to multijoint movements. During performance of multijoint movements, certain
prime movers may take precedence over others, creating
a hypertrophic imbalance between muscles. The use of singlejoint exercises can selectively target underdeveloped muscles,
improving muscular symmetry. Moreover, the unique architecture of individual muscles suggests employing single-joint
movements can elicit differing neuromuscular activation
patterns that heighten overall muscular development (7).
The use of unstable surfaces in a hypertrophy-oriented
routine is generally not supported by research. Resistance
exercise on an unstable surface requires extensive activation of
the core musculature to carry out performance (6,110). This,
in turn, results in significant decreases in force output to the
prime muscle movers. Anderson and Behm (5) found that
force output was 59.6% lower when performing a chest press
on an unstable surface compared to a stable surface. Similarly,
McBride et al. (112) demonstrated significant reductions in
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peak force and rate of force development (by 45.6 and 40.5%,
respectively) when performing a squat on an unstable vs.
stable surface. Such large reductions in force output diminish
dynamic tension to the target muscles, mitigating the
hypertrophic response.
An exception to the use of unstable surfaces in a hypertrophy-oriented routine involves exercises for the core musculature. Sternlicht et al. (164) found that crunches performed
on a stability ball elicited significantly greater muscle activity
in both the upper and lower rectus abdominus than crunches
performed under stable conditions. Similar results were
shown by Vera-Garcia et al. (186), who displayed significantly
increased activity of both the rectus abdominis and the external obliques when performing curl ups on an unstable surface
compared to a stable surface. These results suggest a role for
unstable surface training in developing the abdominals.
Rest Interval
The time taken between sets is referred to as the rest interval.

Rest intervals can be classified into 3 broad categories: short
(30 seconds or less), moderate (6090 seconds), and long (3
minutes or more). The use of each of these categories has
distinct effects on strength capacity and metabolite buildup,
thereby impacting the hypertrophic response (195).
Short rest intervals tend to generate significant metabolic
stress, thereby heightening anabolic processes associated with
metabolite buildup (52). However, limiting rest to 30 seconds
or less does not allow sufficient time for an athlete to regain
muscular strength, significantly impairing muscular performance in subsequent sets (137,141). Thus, the hypertrophic
benefits associated with greater metabolic stress are seemingly counterbalanced by a decreased strength capacity,
making short rest intervals suboptimal for maximizing
hypertrophic gains.
Long rest intervals afford full recovery of strength between
sets, facilitating the ability to train with maximum force
capacity (121). de Salles et al. (32) displayed that rest intervals
of 35 minutes allowed for greater repetitions over multiple
sets when training with loads between 50 and 90% of 1RM.
However, although mechanical tension is maximized by long
rest periods, metabolic stress is compromised (92,94). This
may blunt anabolic drive, attenuating a maximal hypertrophic response.
Moderate rest intervals appear to provide a satisfactory
compromise between long and short rest periods for
maximizing the muscle hypertrophy. Research indicates that
a majority of an athletes strength capacity is recovered within
the first minute after cessation of a set (168). Moreover,
consistently training with shorter rest intervals leads to
adaptations that ultimately allow a lifter to sustain a significantly higher mean percentage of 1RM during training (95).
These adaptations include increased capillary and mitochondrial density and an improved capacity to buffer H+ and
shuttle it out of muscle, thereby minimizing performance
decrements.
2865

Moderate rest intervals also help to enhance the bodys
anabolic environment to a greater extent than longer rest
intervals. For one, moderate rest induces greater hypoxia,
heightening the potential for increased muscular growth
(182). Moderate rest also is associated with a greater metabolic buildup, mediating a large spike in anabolic hormonal
concentrations after exercise (94). However, there is some
evidence that this hormonal advantage is not sustained over
time. Buresh et al. (22) compared the anabolic hormonal
response to routines with rest intervals of 1 vs. 2.5 minutes.
Although the shorter rest intervals had a significantly greater
impact on elevating GH levels in the early stages of the
protocol, the difference in hormonal response was not
significant between routines by end of the fifth week and
was nonexistent by week 10. This suggests a postadaptive
response by the muscles to reduced rest intervals, lending
support to the need for periodization in a hypertrophyoriented resistance training program.
Muscular Failure
Muscular failure can be defined as the point during a set when

muscles can no longer produce necessary force to concentrically lift a given load. Although the merits of training
to failure are still a matter of debate, it is commonly believed
that training to muscular failure is necessary to maximize
the hypertrophic response (196). Several theories have been
proposed in support of this contention.
For one, training to failure is hypothesized to activate
a greater number of MUs (196). When a lifter becomes
fatigued, a progressively greater number of MUs are recruited
to continue activity, providing an additional stimulus for
hypertrophy (145). In this way, failure may provide increased
stimulation to the highest threshold MUs when moderate
repetition ranges are employed.
Training to failure also may enhance exercise-induced
metabolic stress, thereby potentiating a hypertrophic response. Continuing to train under conditions of anaerobic
glycolysis heightens the buildup of metabolites, which in turn
enhances the anabolic hormonal milieu. Linnamo et al. (104)
displayed that performing sets at 10RM to failure caused
a significantly greater postexercise elevation in GH secretion
compared to the same load not performed to failure.
Although training to failure does appear to confer hypertrophic benefits, there is evidence that it also increases the
potential for overtraining and psychological burnout (43).
Izquierdo et al. (76) found that training to failure caused
reductions in resting IGF-1 concentrations and a blunting of
resting testosterone levels over a 16-week protocol, suggesting that subjects may have been overtrained. Thus, although
it seems prudent to include sets performed to failure in
a hypertrophy-oriented program, its use should be periodized and/or limited to avoid an overtrained state.
Repetition Speed
The speed with which a lifter performs repetitions can impact

the hypertrophic response. Despite limitations both in the
2866
the
quantity of research and aspects of study design, some

conclusions can be drawn on the topic.
With respect to concentric repetitions, there is some
evidence that faster repetitions are beneficial for hypertrophy.
Nogueira et al. (133) found that performing concentric
actions at 1-second cadence instead of three seconds had
greater impact on both upper and lower limb muscle thickness in elderly men. This may be attributed to an increased
recruitment and corresponding fatigue of high-threshold
MUs. Other studies, however, suggest that training at moderate speeds has greater effects on hypertrophy (56), perhaps
through a heightened metabolic demand (12). Maintaining
continuous muscle tension at moderate repetition speeds also
has been shown to enhance muscle ischemia and hypoxia,
thereby augmenting the hypertrophic response (174). Training at very slow velocities (i.e., superslow training) has
generally been shown to be suboptimal for the development
of strength and hypertrophy (82,129), and therefore should
not be employed when the goal is to maximize muscle growth.
From a hypertrophy standpoint, speed of movement may
have greater importance on the eccentric component of a
repetition. Although concentric and isometric contractions
have been shown to produce a hypertrophic response, a
majority of studies seem to show that eccentric actions have
the greatest effect on muscle development. Specifically,
lengthening exercise is associated with a more rapid rise in
protein synthesis (122) and greater increases in IGF-1 mRNA
expression (152) compared to shortening exercise. Moreover,
isotonic and isokinetic training that does not include
eccentric contractions result in less hypertrophy than those
that include lengthening contractions (39,68,74).
The hypertrophic superiority of eccentric exercise is largely
attributed to a greater muscular tension under load. It is
theorized that this is because of a reversal of the size principle
of recruitment, which results in fast-twitch fibers being
selectively recruited (152,173). This was demonstrated by
Nardone and Schieppati (128), who showed derecruitment of
the slow-twitch soleus muscle and a corresponding increase
in activity of the gastroc during eccentric plantar flexion
contractions. There is also evidence that eccentric contractions result in additional recruitment of previously inactive
MUs (116,127).
As a result of the excessive stress on a small number of
active fibers, eccentric exercise also is associated with greater
muscle damage when compared to concentric and isometric
contractions (116). This manifests as Z-line streaming, which
current research suggests is indicative of myofibrillar
remodeling (30,204). It has been shown that MyoD
mRNA expression is specifically upregulated by eccentric
contractions (78).
Shepstone et al. (152) found that fast (3.66 radss21) eccentric repetitions resulted in significantly greater hypertrophy
of type II fibers compared to slow (0.35 rads21) repetitions.
This is consistent with the lengthening portion of the force
velocity curve, which shows greater muscle forces are
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the
TM

generated at higher velocities. However, findings of this study
are limited because subjects trained on an isokinetic
dynamometer, which provides a resistive force against the
agonist muscle and is not gravity dependent. Traditional
dynamic constant resistance exercise (i.e., free weights, cable
pulleys, etc.) does not confer such an advantage. Rather,
eccentric contractions are aided by the pull of gravitational
force, requiring the lifter to resist gravity to sustain muscular
tension. Thus, a slower speed of movement is necessary to
maximize the training response (45).
PRACTICAL APPLICATIONS
Current research suggests that maximum gains in muscle
hypertrophy are achieved by training regimens that produce
significant metabolic stress while maintaining a moderate
degree of muscle tension. A hypertrophy-oriented program
should employ a repetition range of 612 reps per set with rest
intervals of 6090 seconds between sets. Exercises should
be varied in a multiplanar, multiangled fashion to ensure
maximal stimulation of all muscle fibers. Multiple sets should
be employed in the context of a split training routine to
heighten the anabolic milieu. At least some of the sets should
be carried out to the point of concentric muscular failure,
perhaps alternating microcycles of sets to failure with those
not performed to failure to minimize the potential for
overtraining. Concentric repetitions should be performed at
fast to moderate speeds (13 seconds) while eccentric
repetitions should be performed at slightly slower speeds
(24 seconds). Training should be periodized so that the
hypertrophy phase culminates in a brief period of highervolume overreaching followed by a taper to allow for optimal
supercompensation of muscle tissue.
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ACKNOWLEDGMENT
18. Bodine, SC, Stitt, TN, Gonzalez, M, Kline, WO, Stover, GL,
Bauerlein, R, Zlotchenko, E, Scrimgeour, A, Lawrence, JC, Glass, DJ,
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skeletal muscle hypertrophy and can prevent muscle atrophy in vivo.
Nat Cell Biol 3: 10141019, 2001.
The author would like to thank Dr. William Kraemer, Dr.

James Eldridge, and Dr. Sue Mottinger for their assistance and
guidance in this research review.
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TM
BREVE RESEA
LOS MECANISMOS DE HIPERTROFIA MUSCULAR Y SU

APLICACIN AL ENTRENAMIENTO DE RESISTENCIA.
BRAD J. SCHOENFELD
Global Fitness Services, Scarsdale, New York
RESUMEN
Schoenfeld, BJ. Los mecanismos de la hipertrofia muscular y
aplicacin al entrenamiento de resistencia. J Strength Cond Res
24 (10): 2857-2872, 2010 El aumento de masa magra
corporal es perseguido extensamente por las personas que
levanten cargas. La investigacin est carente, sin embargo, en
cuanto al mejor mtodo para maximizar el crecimiento
muscular. Los culturistas entrenan, generalmente, con cargas
moderadas e intervalos de descanso bastante cortos, que
inducen altas cantidades de estrs metablico. Los halteras, por
otra parte, entrenan rutinariamente con cargas de alta
intensidad y periodos de descanso muy largos entre series.
Aunque ambos grupos son conocidos por exhibir una
musculatura impresionante, no est claro qu mtodo es mejor
para los aumentos hipertrficos. Se ha demostrado que
muchos factores median el proceso hipertrfico y que la
tensin mecnica, el dao del msculo, y estrs metablico
pueden desempear un papel importante en el crecimiento
muscular inducido por el ejercicio. Por lo tanto, el propsito
de esta resea es doble: (a) repasar extensivamente la literatura
en cuanto a los mecanismos de hipertrofia muscular y su
aplicacin al entrenamiento y (b) para dibujar conclusiones de
la investigacin en cuanto al protocolo ptimo para maximizar
el crecimiento del msculo.
PALABRAS CLAVE: Desarrollo del msculo, respuesta
hipertrfica, crecimiento del msculo, tensin muscular, daos
musculares, estrs metablico.
INTRODUCCIN
El aumento de masa magra corporal es perseguido
extensamente por las personas que levanten cargas. Dada la
correlacin fuerte entre el rea transversal del msculo y la
fuerza muscular (111), el crecimiento de muscular es una meta
fundamental de los atletas implicados en deportes de fuerza y
potencia tales como ftbol, rugby, y halterofilia. La masa
muscular tambin es vital en el deporte del culturismo, donde
juzgan a los competidores en cuanto a la cantidad y la calidad
de su desarrollo muscular. En un nivel ms general, la
hipertrofia del msculo tambin es perseguida por los muchos
levantadores recreacionales que aspiran desarrollar su
constitucin hacia un cuerpo ms voluminoso. Por lo tanto, la
maximizacin de la masa muscular ha alcanzado gran
envergadura por su implicacin en variedad de poblaciones
asociadas a deporte y a salud.
En sujetos no entrenados, la hipertrofia es virtualmente
inexistente durante las etapas iniciales del entrenamiento de
resistencia, y la mayora de ganancias en fuerza son resultado
de las adaptaciones neurales (124). Tras un par de meses de
entrenamiento, sin embargo, la hipertrofia comienza a
convertirse en el factor dominante, donde las extremidades
superiores mostraron su hipertrofia antes que las extremidades
inferiores (124.177). La gentica, la edad, el gnero, y otros
factores han demostrado mediar en la respuesta hipertrfica a
un protocolo de entrenamiento, afectando al ndice y la
cantidad total de aumentos de masa magra muscular (93).
Adems, llega a ser progresivamente ms difcil aumentar la
masa magra del msculo segn se gana experiencia en el

entrenamiento, aumentando la importancia del diseo
rutinario apropiado.
Aunque la hipertrofia muscular se puede lograr a travs de
una amplia gama de programas de entrenamiento de
resistencia, el principio de especificidad dicta que algunas
rutinas promovern mayor hipertrofia que otras (16). La
investigacin est carente, sin embargo, en cuanto al mejor
acercamiento a un programa para alcanzar esta meta. Los
culturistas entrenan, generalmente, con cargas moderadas e
intervalos de descanso bastante cortos, que inducen altas
cantidades de estrs metablico. Los halteras, por otra parte,
entrenan rutinariamente con cargas de alta intensidad y
periodos de descanso muy largos entre series. Aunque ambos
grupos son conocidos por exhibir una musculatura
impresionante, no est claro qu mtodo es mejor para los
aumentos hipertrficos (149) o si otros mtodos de
entrenamiento pueden, quizs, ser mejores. Por lo tanto, el
propsito de esta resea es doble: (a) repasar extensivamente
la literatura en cuanto a los mecanismos de hipertrofia
muscular y su aplicacin al entrenamiento y (b) para dibujar
conclusiones de la investigacin en cuanto al protocolo
ptimo para maximizar el crecimiento del msculo y
desarrollar una rutina especfica de hipertrofia para ello.
TIPOS DE HIPERTROFIA MUSCULAR
La hipertrofia muscular puede considerarse distinta y por
separado de la hiperplasia muscular. Durante la hipertrofia, los
elementos contrctiles se agrandan y la matriz extracelular se
expande para apoyar el crecimiento (187). Esto contrasta con
la hiperplasia, que resulta de un aumento en el nmero de
fibras dentro del msculo. La hipertrofia contrctil puede
ocurrir ya sea mediante la adicin de sarcmeros en serie, o en
paralelo.
La mayora de la hipertrofia consecuente inducida por los
programas de entrenamiento tradicionales de resistencia resulta
de un aumento de sarcmeros y miofibrillas aadidos en
paralelo (135,179). Cuando el msculo esqueltico es sometido
un estmulo de sobrecarga, este causa perturbaciones en los
miocitos y la adyacente matriz extracelular. Esto pone en
marcha una cadena de acontecimientos biognicas, que en
ltima instancia conducen a un aumento en el tamao y
cantidad de las protenas contrctiles del msculo, actina y
miosina, y el nmero total de sarcmeros en paralelo. Esto, a
su vez, aumenta el dimetro de las fibras individuales, lo que a
su vez conduce a un aumento en el rea transversal del
msculo (182).
Un aumento en serie de sarcmeros resulta en una
longitud dada del msculo que corresponde a una corta
longitud del sarcmero (182). La hipertrofia en serie ha
demostrado ser producida cuando el msculo est
obligado a adaptarse a una nueva longitud funcional. Esto se
ve con miembros que se colocan en un molde, donde la
inmovilizacin de un conjunto en largas longitudes musculares
resulta en un aumento del nmero de sarcmeros en serie,
mientras que la inmovilizacin en cortas longitudes causa una
Mecanismos de Hipertrofia Muscular

reduccin (182). Hay algunas pruebas de que ciertos tipos de
ejercicio pueden afectar al nmero de sarcmeros
en serie. Lynn y Morgan (107) demostraron que cuando las
ratas suben en un tapiz rodante (es decir, inclinado), tenan un
menor nmero de sarcmeros en serie que las que descienden
(es decir, declinado). Esto sugiere que las repeticiones slo
excntricas conducen a un mayor nmero de sarcmeros en
serie, mientras que el ejercicio consistente nicamente en
contracciones concntricas resulta en una disminucin de la
longitud del sarcmero en serie.
Se plantea la hiptesis de que la hipertrofia puede crecer
por un aumento de varios elementos no contrctiles y lquido
(108, 205). Esto se ha denominado ''hipertrofia sarcoplsmica'',
y puede resultar en una mayor masa muscular sin
aumento concomitante en la fuerza (154). Los aumentos en
hipertrofia sarcoplsmica se cree que resulta de un tipo de
entrenamiento especfico, una creencia perpetuada por
estudios que muestran que el msculo hipertrofiado es
diferente en los culturistas que en los halteras (179). En
concreto, los culturistas tienden a mostrar una mayor
proliferacin de tejido conectivo fibroso endomisial y
un contenido de glucgeno mayor en comparacin con los
levantadores de potencia (109, 177), presumiblemente a causa
de diferencias en la metodologa de entrenamiento. Aunque la
hipertrofia sarcoplsmica es a menudo descrita como no
funcional, es plausible que las adaptaciones crnicas asociadas
a sus efectos sobre la inflamacin celular pueden
mediar aumentos posteriores en la sntesis de protenas que
conducen a un mayor crecimiento contrctil.
Algunos investigadores han propuesto la posibilidad de
que los aumentos en la seccin transversal pueden ser, al
menos, parcialmente debidos a un aumento en el nmero de
fibras (8). Un meta-anlisis de Kelley (84) encontr que la
hiperplasia se presenta en ciertas especies animales bajo
condiciones experimentales, como resultado de sobrecarga
mecnica. El aumento en el nmero de fibras musculares fue
mayor entre aquellos grupos que utilizaron un modelo aviar
que los que lo hicieron con un modelo de mamfero, y la
sobrecarga de estiramiento produjo mayores aumentos en el
nmero de fibras que el ejercicio. Sin embargo, investigaciones
posteriores sugirieron que tales observaciones pueden ser
errneas. Falta evidencia de que la hiperplasia se produce en
sujetos humanos falta y, en caso de formarse, los efectos
generales sobre el rea transversal del msculo parece ser
mnima (1.108).
LAS CLULAS SATLITE Y LA HIPERTROFIA MUSCULAR
El msculo es un tejido postmittico, lo que significa que no se
somete a un reemplazo celular significativo a lo largo de la
vida. Es necesario, por lo tanto, un mtodo eficaz para la
reparacin celular con el fin de evitar la apoptosis y mantener
la masa sea. Esto se lleva a cabo a travs del equilibrio
dinmico entre la sntesis de protena muscular y la
degradacin (69, 182). La hipertrofia muscular se produce
cuando la sntesis de protena excede la descomposicin de
protenas.
Se cree que la hipertrofia est mediada por la actividad de
las clulas satlite, que reside entre la lmina basal
y el sarcolema (66,146). Estas clulas madre biognicas estn
normalmente inactivas, pero se activan cuando se impone un
estmulo mecnico suficiente sobre el msculo esqueltico
(187). Una vez excitado, las clulas satlite proliferan e instan a
fusionar las clulas existentes o entre ellas mismas para crear
nuevas miofibras, proporcionando los precursores necesarios
para su reparacin y posterior crecimiento de nuevo tejido
muscular (182).
Se piensa que las clulas satlite facilitan la hipertrofia
muscular de varias maneras. Por un lado, dan ncleos extra
para las fibras musculares, aumentando la capacidad de
sintetizar nuevas protenas contrctiles (123). Para que la

proporcin entre el contenido de ncleos musculares y fibras
se mantenga constante durante la hipertrofia, los cambios
requieren una fuente externa de clulas activas en mitosis. Las
clulas satlite conservan la capacidad mittica y sirven as
como una piscina de mioncleos para apoyar el crecimiento
muscular (15). Esto es consistente con el concepto de dominio
mionuclear, que propone que el mioncleo regula la
produccin de ARNm para un volumen sarcoplsmico finito y
cualquier aumento en el tamao de fibra debe estar
acompaado por un aumento proporcional en mioncleos.
Dado que los msculos estn compuestos de mltiples
dominios mionucleares, la hipertrofia podra ocurrir como
resultado de un aumento en el nmero de dominios (a travs
de un aumento del nmero de mioncleos), o de un aumento
en el tamao de los actuales dominios. Se cree que ambos se
producen hipertrofia, con una contribucin significativa de las
clulas satlite (182).
Adems, las clulas satlite coexpresan varios factores
reguladores (incluyendo Myf5, MyoD, miogenes y MRF4) que
ayudan en la reparacin del msculo, la regeneracin y el
crecimiento (27). Estos factores reguladores se unen a la
secuencia de ADN especfica presente en el promotor de genes
musculares, desempeando cada uno papeles distintos en la
miognesis (148.155).
RUTAS MIOGNICAS
La hipertrofia muscular inducida por el ejercicio se ve facilitada
por un nmero de rutas de sealizacin, por lo que los efectos
de la estimulacin mecnica estn molecularmente
transducidas a objetivos que favorecen la sntesis protica
sobre la degradacin. Varios rutas primarias de sealizacin
anablica han sido indentificadas incluyendo Akt / mTOR
(mammalian target of rapamycin), protena-quinasa activada
por mitgenos (MAPK), y rutas calcio-dependientes (Ca2+)
La siguiente es una visin general de cada una de estas vas.
Ruta Akt / mTOR
La va de Akt / mTOR se cree que acta como un maestro
regulador del crecimiento de msculo esqueltico (18,77,181).
Aunque los mecanismos moleculares especficos no han sido
completamente aclarados, Akt es considerado un punto nodal
aferente que es a la vez un efector de sealizacin anablica y
un inhibidor dominante de las seales catablicas (126,182).
Cundo estn activadas las seales del Akt a mTOR, esta ruta
ejerce efectos sobre varios objetivos intermedios que
promueven la hipertrofia en el tejido muscular.
Ruta protena-quinasa activada por mitgenos (MAPK),
La MAPK es una ruta reguladora de la expresin gnica, el
estado redox y el metabolismo (88). Especficamente en la
hipertrofia muscular inducida por el ejercicio, la MAPK ha
demostrado ligar el estrs celular a una respuesta adaptativa de
los miocitos, para modular el crecimiento y diferenciacin
(147). Tres diferentes mdulos de sealizacin MAPK
se asocian con hipertrofia muscular inducida por el ejercicio:
extracelulares reguladas por seales quinasas (ERK 1/2), p38
MAPK, y c-Jun NH2-terminal quinasa (JNK). De estos
mdulos, JNK ha demostrado ser el mayor responsable del
estrs mecnico y el dao muscular, y es particularmente
sensible al ejercicio excntrico. La activacin de JNK Inducida
por el ejercicio est relacionada con un rpido aumento en el
ARNm de los factores de transcripcin que modulan la
proliferacin celular y la reparacin del ADN (9,10).
Rutas calcio-dependientes (Ca2+)
Varias de ellas han sido implicadas en la regulacin de la
hipertrofia muscular. Calcineurina (Cn), una fosfatasa
reguladora del Ca2+, se cree que es un regulador crtico en las
Journal of Strength and Conditioning Research the TM | www.nsca-jscr.org

cascadas de liberacin de Ca2+. La Cn acta eferentemente en
la va de Ca2+ y media en diferentes efectores hipertrficos,
tales como el factor 2 de mejora de los miocitos, factores de
transcripcin GATA, y el factor nuclear de activacin de los
tbulos T (118). La va Cn-dependiente est relacionada con la
hipertrofia de todo tipos de fibras, y su inhibicin se ha
demostrado para prevenir el crecimiento muscular incluso en
presencia de sobrecarga muscular (35,36).
HORMONAS Y CITOQUINAS
Las hormonas y citoquinas desempean un papel integral en la
respuesta hipertrfica, sirviendo como reguladores aferentes de
los procesos anablicos. Elevadas concentraciones de
hormonas anablicas aumentan la probabilidad de
interacciones con el receptor, facilitando el metabolismo de las
protenas y el posterior crecimiento muscular (31). Muchas
tambin estn involucrados en la proliferacin y diferenciacin
de celulas satlite, y quizs facilitan la unin de estas clulas a
las fibras daadas para ayudar en la reparacin muscular (182,
187).
La regulacin hormonal de la hipertrofia es compleja, con
la creencia de que muchas hormonas y citoquinas contribuyen
a la respuesta. El hepato-factor de crecimiento, interleucina-5
(IL-5), interleucina- 6 (IL-6), factor de crecimiento de
fibroblastos, y el factor inhibidor de leucemia han demostrado
promover el anabolismo (162, 182, 187). Tambin se ha
demostrado que la insulina tambin posee propiedades
anabolizantes, con mayores efectos en la atenuacin
proteltica (catabolismo proteico) que en el aumento la
sntesis de protenas (anabolismo proteco). Tambin se cree
que la insulina induce la mitosis y la diferenciacin de las
clulas satlite (187). Los niveles de insulina descienden durante
el ejercicio, sin embargo, no es un aspecto modificable de un
rgimen de ejercicio y por lo tanto no se abordar aqu.
Varios tipos de ejercicio han demostrado causar agudas,
y en algunos casos crnicas, alteraciones hormonales que
parecen desempear un papel en la mediacin de los sistemas
de sealizacin hipertrficos (119). Las 3 hormonas ms
estudiadas de estas son el factor insulnico de crecimiento (IGF1), la testosterona, y la hormona del crecimiento (GH STH).
Si la respuesta hormonal aguda al ejercicio proporciona un
estmulo anablico significativo, ha sido un tema cuestionado
por algunos investigadores (191, 194), sin embargo, con
las inherentes limitaciones experimentales en estos estudios y
sin un mayor nmero de evidencias bsicas y aplicadas para
demostrar lo contrario, afirmar la importancia de los cambios
hormonales en las adaptaciones fisiolgicas que resultan de
ejercicios de resistencia durante un perodo de entrenamiento
es prematuro y sin contexto.
Factor insulnico de crecimiento (IGF-1)
El factor insulnico de crecimiento es definido a menudo como
la hormona anablica ms importante en mamferos. Se cree
que proporciona la respuesta anablica principal para el
cuerpo como un todo y muestra efectos mejorados en
respuesta a cargas mecnicas (19, 63). Estructuralmente, el IGF1 es una hormona peptdica, nombrada as por sus similitudes
estructurales a la insulina. Los factores de crecimiento del IGF-1
se encuentran en clulas satlite activas, miofibras adultas, y
clulas de Schwann (15). Durante el ejercicio, los msculos no
slo producen ms IGF-1 de manera sistemtica que el hgado,
sino que tambin utilizan ms IGF-1 circulante (49). La
disponibilidad del IGF-1 para el msculo es controlada por
protenas ensambladoras de IGF-1 (IGFBP), que estimulan o
inhiben los efectos de IGF-1 despus de la unin a una IGFBP
especfica (182).
Han sido identificadas tres isoformas distintas de IGF-1: las

formas sistmicas IGF-1Ea e IGF-1Eb, y una variante de unin,
el IGF-1Ec. Aunque las 3 isoformas se encuentran en tejido
intramuscular, slo la IGF-1Ec parece ser activada por seales
mecnicas (63, 199). Debido a su respuesta a la estimulacin
mecnica, IGF-1Ec es familiarmente conocida como factor de
crecimiento mecnico (MGF).
Aunque los mecanismos exactos de accin de IGF-1 no se
han aclarado por completo, se cree que la estimulacin
mecnica hace que el gen de IGF-1 se una al MGF, que a su vez
inicia la hipertrofia muscular. En un da ms o menos, el MGF
queda unido completamente con las isoformas sistmicas del
IGF-1 (IGF-1Ea e IGF-1Eb) (54, 69). A partir de entonces, los
niveles de IGF-1 permanecen elevados en el tejido muscular
durante algn tiempo, con efectos miognicos vistos hasta 72
horas despus del ejercicio (117). Aunque el MGF ha
demostrado ser particularmente sensible al dao muscular, no
est claro si la isoforma se regula positivamente por dao de la
membrana o si el dao de la membrana inicia la produccin
de MGF (48).
Se ha demostrado que el IGF-1 induce hipertrofia tanto en
forma autocrina como paracrina (34) y ejerce sus efectos en
mltiples formas. Por un lado, el IGF-1 promueve directamente
el anabolismo mediante el aumento de la tasa de sntesis de
protenas en fibras musculares diferenciadas (15,63). Por otra
parte, se ha demostrado que la aparicin de MGF local activa
clulas satlite y media en su proliferacin y diferenciacin (69,
200). Por otro lado, se piensa que la isoforma IGF-IEA mejora
la unin de clulas de satlite con las fibras musculares,
facilitando la donacin de mioncleos y ayudando a mantener
las proporciones ptimas entre ADN y protenas en el tejido
muscular (182).
El factor insulnico de crecimiento tambin produce la
activacin gentica de los canales L de calcio, lo que resulta en
un aumento intracelular de la concentracin de Ca2+ (125).
Esto conduce a la activacin de mltiples rutas anablicas
calcio-dependientes, incluyendo calcineurina (Cn) y sus
numerosos objetivos de sealizacin eferente.
Testosterona
La testosterona es una hormona derivada del colesterol que
tiene un efecto anablico considerable sobre el tejido muscular
(33, 105). Adems de sus efectos sobre el msculo, la
testosterona tambin puede interactuar con los receptores de
las neuronas y, por lo tanto, aumentar la cantidad de
neurotransmisores liberados, regenerar los nervios y aumentar
el tamao de las clulas del cuerpo.
La mayor parte de la testosterona es sintetizada y
secretada por las clulas de Leydig de los testculos a travs del
eje hipotlamo-hipofisario-gonadal, con pequeas cantidades
derivadas de los ovarios y glndulas suprarrenales (22). En la
sangre, la gran mayora de testosterona se encuentra unida a la
albmina (38%) o a hormonas esteroides como globulina
(60%), quedando el 2% restante circulando en un estado sin
consolidar (forma libre). A pesar de que slo la forma libre es
biolgicamente activa y est disponible para su uso por los
tejidos, la testosterona unida (no libre) puede activarse
mediante la rpida disociacin de la albmina (105). La
testosterona libre se une a receptores andrognicos de los
tejidos diana, que se encuentran en la clulas de citoplasma.
Esto causa un cambio conformacional que transporta la
testosterona hasta el ncleo de la clula, donde interacta
directamente con el ADN cromosmico.
Aunque los efectos de la testosterona en el msculo se
muestran en ausencia de ejercicio, sus acciones se magnifican
con cargas mecnicas, promoviendo el anabolismo, tanto
mediante el aumento de la tasa de sntesis proteica, como por
la inhibicin de la degradacin de protenas (22). La
testosterona tambin puede contribuir a la acumulacin de
protenas indirectamente estimulando la liberacin de otras

hormonas anablicas como GH (31). Adems, se ha
demostrado que promueve la replicacin y activacin de
clulas satlite, lo que resulta en un aumento del nmero de
clulas satlite miogenticamente producidas (155). Se ha
demostrado que la supresin de compromete seriamente la
respuesta a ejercicio de resistencia (100).
Tambin se ha demostrado que el entrenamiento de
resistencia optimiza y regula positivamente el contenido de
receptores andrognicos en los seres humanos (13, 80). En los
roedores, la modulacin de los receptores andrognicos parece
tener lugar en un tipo de fibra de una manera especfica, con
incrementos especficos en los msculos de contraccin rpida(20). Esto conllevara la mejora en el potencial de unin de la
testosterona a nivel celular, y por tanto, facilitara su absorcin
en los tejidos diana.
El ejercicio de resistencia puede tener un sustancial efecto
agudo en la secrecin de testosterona. Ahtiainen et al. (2)
encontraron importantes correlaciones entre las elevaciones de
testosterona inducidas por el entrenamiento y el rea
transversal del msculo, algo que sugiere que las elevaciones
agudas de la testosterona inducidas por el ejercicio pueden
jugar un papel importante en la hipertrofia muscular. Sin
embargo, estas respuestas agudas son limitadas en las mujeres y
los ancianos, mitigando el potencial hipertrfico en estas
poblaciones (61, 90, 130).
Los efectos crnicos del entrenamiento de resistencia sobre
las concentraciones de testosterona totales del cuerpo no estn
claros hasta la fecha. Aunque algunos estudios muestran un
aumento sostenido como resultado del ejercicio de resistencia
(60, 93, 163), otros muestran poco o ningn cambio (31,42).
Se necesitan ms investigaciones para mejorar el conocimiento
sobre este tema.
Hormona del crecimiento (GH o STH)
La hormona del crecimiento es una hormona polipeptdica,
que se considera que tiene propiedades anablicas y
catablicas. Especficamente, la GH acta como un agente
distribuidor que induce el metabolismo de las grasas a travs
de la movilizacin de triglicridos, y estimula la captacin
celular e incorporacin de aminocidos en varias protenas,
incluyendo el msculo (187). En ausencia de carga mecnica,
La GH sobrerregula preferentemente el ARNm del IGF-1
sistmico, y media en la expresin gentica del IGF-1 no
heptico de una forma autocrina / paracrina (63).
La hormona del crecimiento es secretada por la glndula
pituitaria anterior y se libera de una manera pulstil,
mostrando que las mayores secreciones no derivadas del
ejercicio ocurren durante el sueo. Han sido identificadas ms
de 100 isoformas moleculares de GH; sin embargo, la mayora
de los estudios de entrenamiento de resistencia se han
centrado exclusivamente en la isoforma 22-kDa, limitando las
posibles conclusiones. Investigaciones recientes sugieren una
liberacin preferencial de mltiples isoformas de GH con vidas
medias prolongadas durante el ejercicio, lo que permite su
accin sostenida sobre los tejidos diana (131).
Adems de ejercer efectos sobre el tejido muscular, la GH
est tambin involucrada en la regulacin de la funcin
inmunolgica, la remodelacin sea, y el volumen de fluido
extracelular. En total, la GH est implicada como promotora
de ms de 450 acciones en 84 tipos de clulas (190).
Los niveles de la hormona del crecimiento crecer
considerablemente tras la realizacin de varios tipos de
ejercicio (96). Ha sido altamente correlacionado un
incremento de GH inducido por el ejercicio con la magnitud
de hipertrofia muscular en fibras tipo I y tipo II (113). Se
postula que un aumento transitorio de GH puede conducir a
una mayor interaccin con los receptores de clulas
musculares, facilitando la recuperacin muscular y la
estimulacin de una respuesta hipertrfica (134). Se cree
tambin que la hormona del crecimiento participa en la el

aumento de formacin local de IGF-1 inducida por el ejercicio
(75). Cuando se combina con el ejercicio intenso, la liberacin
de GH est asociada con una marcada sobrerregulacin del
gen del IGF-1 en el msculo, de modo que ms GH se une con
la isoforma MGF (63).
Algunos investigadores se han preguntado si lo que la GH
hace, de hecho, tiene un efecto significativo sobre la
hipertrofia de tejido muscular (143). Este punto de vista se
basa en los resultados de varios estudios que no han
encontrado un aumento significativo de la masa muscular
cuando la GH se administra como parte de un protocolo de
entrenamiento de resistencia (101, 201-203). Sin embargo,
estos protocolos no explicaron los grandes picos de GH vistos
en el post-entrenamiento, ni tuvieron en cuenta el trnascurso
de tiempo de la elevacin de GH en conjuncin con el dao
muscular. Por lo tanto, es imposible sacar conclusiones a partir
de estos estudios en cuanto a si una respuesta de la GH
inducida por el ejercicio se asocia con el anabolismo del
msculo esqueltico. Todava no estn muy claras las acciones
anablicas de la GH, y an se necesitan ms investigaciones
para dilucidar plenamente su papel en el desarrollo muscular.
INFLAMACIN CELULAR
La hidratacin celular (es decir, la inflamacin celular) sirve
como un regulador fisiolgico de la funcin celular (65). Es
conocido por simular procesos anablicos, tanto a travs de
incrementos en la sntesis de protenas como en la
disminucion de la tasa de proteolisis (53, 120, 165). Aunque
debe ser an determinada la base fisiolgica que une la
inflamacin celular con un conductor anablico, es concebible
que una mayor presin contra la membrana se percibe como
una amenaza a la integridad celular, que a su vez hace que la
clula inicie una respuesta de sealizacin que en ltima
instancia conduce a un refuerzo de su ultraestructura.
Se ha demostrado que una clula hidratada inicia un
proceso que implica la activacin de vas de sealizacin de
protena-quinasa en el msculo, y posiblemente media en los
efectos autocrinos de los factores del crecimiento en la
sealizacin de la respuesta anablica como respuesta al
estiramiento de la membrana (106). El estiramiento de la
membrana inducido por la inflamacin celular tambin puede
tener un efecto directo sobre los sistemas de transporte de
aminocidos, mediado a travs de un sensor de volumen
integro-asciado. El fosfatidilinositol-3-quinasa parece ser un
componente de sealizacin importante en la modulacin del
transporte
de
glutamina
y
del
cido
alfa
(metil)aminoisobutrico en el msculo debido a la inflamacin
celular (106).
Se ha demostrado que el ejercicio de resistencia induce
alteraciones del equilibrio hdrico agua intra y extracelular
(156), en la medida de que depende del tipo de ejercicio y la
intensidad del mismo. La inflamacin celular se maximiza por
el ejercicio que se basa en gran medida en la gluclisis, con la
acumulacin de lactato resultante actuando como el principal
contribuyente a los cambios osmticos en el msculo
esqueltico (41, 157). Las fibras de contraccin rpida son
particularmente sensibles a los cambios osmticos, algo
relacionado, presumiblemente, con una alta concentracin de
los canales de transporte de agua llamados acuaporina-4. Los
acuaporina-4 se encuentran fundamentalmente en el sarcolema
de las fibras glucolticas y glucoltico-oxidativas de contraccin
rpidos de los mamferos, lo que facilita la afluencia de fluido
hacia la clula. Dado que las fibras de contraccin rpida son
ms sensibles a hipertrofia, es concebible que a hidratacin
celular aumenta la respuesta hipertrfica durante el
entrenamiento de resistencia que depende en gran medida de
la gluclisis anaerbica.

Regmenes de ejercicios que provocan un aumento de la
capacidad de almacenamiento de glucgeno tambin tienen el
potencial para aumentar la inflamacin celular. Dado que el
glucgeno atrae tres gramos de agua por cada gramo de
glucgeno (25), esto puede reflejar un aumento de capacidad
para la sntesis de protenas en los que poseen una mayor
reserva intramuscular de glucgeno.
HIPOXIA
Se ha demostrado que la hipoxia contribuye a aumentos
hipertrficos del msculo, siendo esto observado incluso en
ausencia de ejercicio. Takarada et al. (172) encontr que 2
sesiones diarias de oclusin vascular atenu significativamente
la atrofia muscular en un grupo de pacientes obligados a
guardar reposo en cama. Hallazgos similares fueron
observados por Kubota et al. (62, 98), donde la oclusin
confiri un efecto protector sobre la fuerza muscular y el rea
transversal del msculo durante un periodo de 2 semanas de
inmovilizacin de una pierna.
Cuando se combina con el ejercicio, la hipoxia parece
tener un efecto aditivo sobre la hipertrofia. Esto fue
demostrado por Takarada et al. (173), quienes utilizaron para
el estudio 24 mujeres mayores divididas en 3 subgrupos:
ejercicio de flexin del codo de baja intensidad (alrededor del
50% de 1 repeticin mxima [1RM]) con oclusin vascular,
ejercicio de flexin del codo de baja intensidad (alrededor del
50% de 1 repeticin mxima [1RM]) sin oclusin vascular, y
ejercicio de flexin del codo de intensidad media (alrededor
del 80% de 1 repeticin mxima [1RM]) sin oclusin vascular.
Despus de 16 semanas, el grupo que realiz entrenamiento de
baja intensidad con oclusin mostr un rea transversal
significativamente mayor en los msculos flexores del codo en
comparacin con el grupo de ejercicio de baja intensidad sin
oclusin. Adems, las ganancias hipertrficas realizadas fueron
similares a las experimentadas por el grupo de ejercicio de
intensidad media.
Hay varias teoras en cuanto a los beneficios del potencial
hipertrfico inducidos por la hipoxia muscular. Por un lado, se
ha demostrado que la hipoxia causa un aumento de la
acumulacin de lactato y reduce agudamente la tasa de
aclaramiento de lactato (173). Esto puede influir en el aumento
de inflamacin celular, que se ha demostrado que regula al
alza la sntesis de protenas. Adems, el aumento en el lactato
puede mediar en elevaciones de hormonas anablicas y
citoquinas. Takarada et al. (172) seal un aumento del 290%
en los niveles de GH tras ejercicio hipxico de baja intensidad
y un aumento en la concentracin de la citoquina muscular IL6, que se mantuvo durante 24 horas post-ejercicio.
Otro mecanismo potencial de la hipertrofia inducida por
hipoxia es su efecto sobre la actividad de especies reactivas del
oxgeno (ROS). Se ha demostrado que la produccin de
especies reactivas del promueve el crecimiento tanto en el
msculo liso como en el msculo cardaco (170), y se teoriza
que tiene efectos hipertrficos similares en el msculo
esqueltico (171). El xido ntrico, un ROS producido durante
el ejercicio, favorece la proliferacin de clulas satlite, que
presumiblemente conduce a un mayor crecimiento del msculo
esqueltico (81, 174). Tambin se ha demostrado que las
especies de oxgeno reactivo generadas durante el
entrenamiento de resistencia activan la sealizacin de MAPK
en mioblastos esquelticos (83), modulando potencialmente
una respuesta hipertrfica.
La hipoxia tambin puede promover efectos hipertrficos
de hiperemia reactiva (es decir, aumento del flujo sanguneo)
tras ejercicio isqumico (173). La hiperemia en el msculo
daado hara concebible permitir la entrega de agentes
anablicos endocrinos y factores de crecimiento a las clulas
satlite, regulando de ese modo su proliferacin y posterior
fusin en miotubos (187).
INICIACIN
A
LA
HIPERTROFIA
MUSCULAR
INDUCIDA POR EL EJERCICIO
Se plantea la hiptesis de que 3 factores primarios son
responsables de iniciar la respuesta hipertrfica al ejercicio de
resistencia: tensin mecnica, dao muscular y la tensin
metablica (38, 79, 153, 185). La siguiente es una visin
general de cada uno de estos factores.
Tensin mecnica
La tensin mecnica inducida producida tanto por la
generacin de fuerzas como por el estiramiento se considera
esencial para el crecimiento muscular, y la combinacin de
estos estmulos parece tener un pronunciado efecto aditivo
(48, 72, 185). Ms especficamente, la sobrecarga mecnica
aumenta la masa muscular mientras que la disminuye en la
atrofia (47). Este proceso parece estar controlado en gran
parte por la tasa de sntesis de protenas durante la iniciacin
del movimiento (11,87).
Se cree que la tensin asociada al entrenamiento de
resistencia perturba la integridad del msculo esqueltico,
causando respuestas moleculares y celulares transducidas
mecano-qumicamente en miofibras y clulas satlite (182). La
sealizacin aferente, se cree que es producida por una cascada
de eventos que involucran factores de crecimiento, citoquinas,
canales activados por estiramiento, y complejos de adhesin
focal (23, 48, 162). La evidencia sugiere que el proceso
aferente est regulado a travs de la ruta Akt / mTOR, ya sea
mediante interaccin directa o mediante la modulacin de
produccin de cido fosfatdico (72, 73). En este punto, sin
embargo, la investigacin no ha proporcionado una
comprensin clara de cmo se llevan a cabo estos procesos.
Durante las contracciones excntricas, se desarrolla tensin
muscular pasiva debido a la prolongacin de los elementos
extra-miofibrilares, especialmente colgeno contenido en la
matriz extracelular y titina (182). Esto aumenta la tensin
activa desarrollada por los elementos contrctiles,
produciendo a su vez la mejora de la respuesta hipertrfica.
Tanto la amplitud y la duracin de acoplamiento de excitacin
es determinada por la frecuencia de estimulacin de la unidad
motora (MU), en la medida de que se cree que codifican las
seales a diversas rutas eferentes como la calcineurinafosfatasa-calmodulina-Ca2+, CaMKII, y CaMKIV, y PKC (26).
Estas vas ayudan a determinar la expresin gnica, acoplando
la excitacin muscular con la transcripcin (182).
La tensin pasiva produce una respuesta hipertrfica que
es especfica del tipo de fibra, con un efecto observado en
contraccin rpida pero no en fibras de contraccin lenta. Esto
fue demostrado por Prado et al. (139), quien encontr que las
fibras de contraccin lenta en conejos exhiban baja tensin
pasiva en la titina, pero la tensin era altamente variable en las
fibras de contraccin rpida.
A pesar de que la tensin mecnica por s sola puede
producir hipertrofia muscular, es poco probable que sea la
nica responsable de ganancias hipertrficas asociadas al
ejercicio (79). De hecho, ciertas rutinas de entrenamiento de
resistencia que emplean altos grados de tensin muscular han
demostrado inducir en gran medida adaptaciones neurales sin
hipertrofia resultante (28. 188).
Dao muscular
El ejercicio fsico puede resultar en daos localizados en el
tejido msculo que, en determinadas condiciones se teoriza,
podran generar una respuesta hipertrfica (38, 69). El dao
puede ser especfico en unas pocas macromolculas de tejido o
ms global en grandes unidades del sarcolema, lmina basal y
tejido conectivo de apoyo, e induce lesiones a elementos
contrctiles y el citoesqueleto (187). Debido a que los
sarcmeros ms dbiles se encuentran en diferentes regiones de
cada miofibrilla, los alargamientos no uniformes provocan un

corte de miofibrillas. Esto deforma las membranas, en
particular los tbulos T, conduciendo a una perturbacin de la
homeostasis del calcio y el consiguiente dao a causa de la
rotura de las membranas y/o apertura de los canales activados
por estiramiento (4).
La respuesta al miotrauma (dao muscular) ha sido
asociada con la respuesta inflamatoria aguda a la infeccin.
Cuando el dao es percibido por el cuerpo, los neutrfilos
migran a la zona de microtraumatismo y las fibras daadas
liberan agentes que atraen macrfagos y lnfocitos. Los
macrfagos eliminan los desechos celulares para ayudar a
mantener la ultraestructura de la fibra y producir citoquinas
que activen mioblastos, macrfagos y linfocitos. Esto se cree
que conduce a la liberacin de varios factores de crecimiento
que regulan la proliferacin y diferenciacin de clulas satlite
(182, 187).
Adems, el rea bajo la unin neuromuscular contiene
una alta concentracin de clulas satlite que, se ha
demostrado, median en el crecimiento muscular (69, 155). Esto
da credibilidad a la posibilidad de que los nervios que inciden
en las fibras daadas podran estimular la actividad de clulas
satlite, promoviendo as hipertrofia (187).
Estrs metablico
Numerosos estudios apoyan un papel anablico del estrs
metablico inducido por el ejercicio (145, 149, 161) y algunos
especularon con que la acumulacin de metabolitos puede ser
ms importante que el desarrollo de la fuerza mxima en la
optimizacin de la respuesta hipertrfica al entrenamiento
(153). Aunque el estrs metablico no parece ser un
componente esencial de las funciones de crecimiento muscular
(40), un gran nmero de evidencias demuestran que puede
tener un efecto hipertrfico significativo, ya sea de manera
primaria o secundaria. Esto puede ser observado
empricamente examinando los regmenes de entrenamiento
de intensidad moderada adoptados por muchos culturistas,
que estn destinados a aumentar el estrs metablico a la vez
que se mantiene una tensin muscular significativa.
El estrs metablico se manifiesta como resultado del
ejercicio basado en gluclisis anaerbica para la produccin de
ATP, lo que resulta en la acumulacin subsiguiente de
metabolitos tales como el lactato, ion hidrgeno, fosfato
inorgnico, creatina, y otros (169, 178). Tambin se ha
demostrado que la isquemia muscular tambin produce estrs
metablico importante, y potencialmente produce un efecto
hipertrfico aditivo cuando se combina con entrenamiento
glucoltico (136. 182). Los mecanismos teorizados de estrs
inducido para mediar la respuesta hipertrfica incluyen
alteraciones en el entorno hormonal, inflamacin celular,
produccin de radicales libres, y aumento de la actividad de
factores de transcripcin orientados hacia el crecimiento (50,
51, 171). Tambin se ha planteado la hiptesis de que un
ambiente ms cido promovido por el entrenamiento
glucoltico puede conducir al aumento de degradacin de las
fibra y una mayor estimulacin de la actividad del nervio
simptico, aumentando as la mediacin para conseguir una
respuesta hipertrfica adaptativa (22).
VARIABLES DE ENTRENAMIENTO E HIPERTROFIA
Consistente en el principio de especificidad, la manipulacin
apropiada de las variables de entrenamiento es esencial para
maximizar la hipertrofia muscular inducida por el ejercicio. La
siguiente es una revisin de cmo cada variable impacta en la
respuesta hipertrfica con respecto a las variables fisiolgicas
previamente tratadas.
Intensidad
La intensidad (es decir, la carga), se ha demostrado, tiene un
impacto significativo en la hipertrofia muscular y podra
decirse que es la variable del entrenamiento ms importante
en la estimulacin del crecimiento muscular (42). La intensidad
es comnmente expresada como porcentaje de 1RM equivale
al nmero de repeticiones que se pueden realizar con un peso
determinado. Las repeticiones pueden clasificarse en tres
rangos bsicos: bajas (1-5), medias (6-12) y altas (15+). Cada
uno de los rangos supondr el uso de diferentes sistemas de
energa y utilizar el sistema neuromuscular de diferentes
maneras, impactando en la medida de la respuesta
hipertrfica.
Ha sido probado que el uso de altas repeticiones, frente a
repeticiones moderadas o bajas, disminuye la obtencin de
posibles aumentos en la hipertrofia muscular (24,71). En
ausencia de isquemia inducida artificialmente (es decir,
entrenamiento
de
oclusin),
una
carga
menor,
aproximadamente, al 65% de 1 RM no se considera suficiente
para promover una hipertrofia sustancial (115). Aunque el
entrenamiento a altas repeticiones puede producir
significativos estrs metablico, la carga es insuficiente para
reclutar y fatigar el mayor nmero posible de unidades
motoras (MUs).
Si las repeticiones bajas o moderadas evocan una mayor
respuesta hipertrfica ha sido un tema de debate, y ambas
producen ganancias significativas en el crecimiento muscular
(24). Sin embargo, hay una creencia general que un rango
moderado de, aproximadamente, 6-12 repeticiones optimiza la
respuesta hipertrfica (86, 89, 205).
La superioridad anablica de un nmero de repeticiones
medio se ha atribuido a factores asociados al estrs
metablico. Aunque las series de bajas repeticiones se llevan a
cabo, casi exclusivamente, por el sistema de la fosfocreatina,
los esquemas de repeticiones moderadas confan en gran
medida en la gluclisis anaerbica (144). Esto da como
resultado una acumulacin significativa de metabolitos.
Estudios de rutinas culturistas de ejercicio realizados con varias
series de 6-12 repeticiones muestran importantes descensos
post-ejercicio en el ATP, la fosfocreatina y el glucgeno, junto
con un notable incremento del lactato en sangre, lactato
intramuscular, glucosa y glucosa-6-fosfato (37, 178). La
acumulacin de estos metabolitos ha demostrado tener un
impacto significativo en los procesos anablicos (96). Por
tanto, es concebible que hay un umbral mximo para la
hipertrofia inducida por la tensin muscular, por encima del
cual los factores metablicos son ms importantes que los
aumentos adicionales de carga.
La acumulacin metablica resultante del entrenamiento
realizado en rangos de repeticiones medias ha mostrado
maximizar la respuesta hormonal anablica aguda del
ejercicio. Tanto la testosterona como la GH son notablemente
elevadas a un mayor grado con rutinas en las que se emplean
series de repeticiones medias, en comparacin con aquellas
rutinas de series realizadas a repeticiones bajas (57, 90, 92, 94,
114), aumentando as el potencial para las interacciones
celulares eferentes que facilitan la remodelacin de tejido
muscular.
Entrenar en un rango de repeticiones moderadas tambin
maximiza la hidratacin celular aguda. Durante el
entrenamiento de repeticiones medias, las venas que
transportan la sangre desde los msculos activos se
comprimen, mientras que las arterias continan entregando
sangre a los msculos activos, creando de ese modo un
aumento de la concentracin de plasma sanguneo
intramuscular. Esto hace que el plasma se filtre fuera de los
capilares y entre en los espacios intersticiales. La acumulacin
de lquido en los espacios intersticiales causa un gradiente de
presin extracelular, lo que provoca un retorno de flujo
plasmtico que entra en el msculo causando el fenmeno

denominado comnmente como contraccin. Esto se ve
aumentado por la acumulacin de subproductos metablicos,
cuya funcin como osmolitos, impulsan fluidos al interior de la
clula (157). Si la inflamacin celular inducida por el ejercicio
media en la hipertrofia muscular no es del todo sabido, pero
parece plausible dado el papel conocido de la hidratacin en
la regulacin de la funcin celular.
Adems, el tiempo extra bajo tensin asociado a un
esquema de repeticiones moderadas en comparacin con un
esquema de repeticiones bajas, aumentara tericamente el
potencial de microtraumatismos y fatigabilidad en todo el
espectro de fibras musculares. Esto parece tener mayor
aplicacin en la hipertrofia de las fibras musculares de
contraccin lenta, que tienen una mayor capacidad de
resistencia que las fibras de contraccin rpida y, por lo tanto,
se beneficiaran de un mayor tiempo bajo tensin. Aunque las
fibras de contraccin lenta no son tan responsables del
crecimiento muscular como las de contraccin rpida, no
quiere decir que no se hipertrofien cuando se las somete a un
estmulo de sobrecarga. Dado que la mayora de los msculos
exhiben importantes perfiles de contraccin lenta (55. 102),
esto puede ayudar potencialmente a maximizar la
circunferencia muscular general.
Algunos investigadores han postulado que los msculos
que contienen un mayor porcentaje de fibras de contraccin
lenta podran tener mayor respuesta hipertrfica a un rango de
repeticiones ms alta, mientras que los msculos de
contraccin rpida responderan mejor a repeticiones bajas
(138. 192). Aunque este concepto es interesante, una receta del
tipo de fibra con respecto al rango de repeticiones no ha sido
confirmada por las investigaciones. Adems, dada la
variabilidad de la composicin del tipo de fibras entre los
individuos, sera difcil o imposible determinar las
proporciones de los tipos de fibras sin una biopsia muscular, lo
que es inviable para la gran mayora de personas.
Volumen
Una serie puede definirse como el nmero de repeticiones
que se realizan consecutivamente sin descanso, por lo que el
volumen de entrenamiento se puede definir como el nmero
total de repeticiones, series, y carga movilizada durante una
sesin de entrenamiento. Se ha demostrado que los protocolos
de alto volumen y multiseries son superiores frente a
protocolos de una sola serie con respecto al aumento de la
hipertrofia (97, 197).
No est claro si la superioridad hipertrfica de los
entrenamientos de mayor volumen es producto del mayor
tiempo total de tensin muscular, dao muscular, estrs
metablico, o alguna combinacin de estos factores. Los
estilos de programas culturistas de un alto volumen de
entrenamiento que genera actividad glucoltica han
demostrado elevar notablemente los niveles de testosterona
que las rutinas de bajo volumen (92,94). Schwab et al. (150)
mostraron que la testosterona aument significativamente
durante la ejecucin de sentadillas hasta despus de la
finalizacin de la cuarta serie, lo que indica un claro beneficio
de las rutinas mulitseries en este respecto.
Los programas de mayor volumen programas tambin
han demostrado mediar la liberacin aguda de GH, en
particular en las rutinas diseadas para aumentar el estrs
metablico (70). Una gran cantidad de investigaciones
muestran que protocolos multiseries provocan una mayor
respuesta de la GH que los protocolos uni-series. (29.124).
Smilios et al. (158) compar, entre hombres jvenes, la
respuesta de la GH a una rutina de fuerza mxima (MS)
consistente 5 repeticiones al 88% de 1RM y 3 minutos de
descanso, frente a una rutina de hipertrofia mxima (MH)
consistente en 10 repeticiones al 75% de 1RM y 2 minutos de
descanso. La GH se midi despus de las series 2, 4, 6. Los
niveles de GH fueron significativamente mayores despus de la

rutina a 4 series, en comparacin con la rutina a 2 series en
MH, pero no en la MS, lo que indica una superioridad de las
rutinas de mayor volumen en cuanto a generar la acumulacin
de metabolitos.
Una rutina de cuerpo partido donde se realizan mltiples
ejercicios para cada grupo muscular en una sesin puede
ayudar a maximizar la respuesta hipertrfica (86). En
comparacin con rutinas de cuerpo entero, una rutina dividida
permite mantener un volumen semanal de entrenamiento con
un menor nmero de series realizadas por sesin de
entrenamiento y ofrece una mayor recuperacin entre sesiones
(85). Esto puede permitir el uso de cargas ms pesadas en el
entrenamiento diario, y as generar una mayor tensin
muscular. Por otra parte, las rutinas divididas pueden servir
para aumentar el estrs metablico muscular, prolongando el
estmulo de entrenamiento en un determinado grupo
muscular, aumentando potencialmente secreciones agudas de
hormonas anablicas, inflamacin celular, e isquemia muscular.
Para maximizar la hipertrofia, existen evidencias de que el
volumen de debe aumentarse progresivamente durante un
determinado ciclo periodizado, culminando en un breve
periodo de sobrecarga o agotamiento. La sobrecarga se puede
definir como un aumento a corto, planificado, en el volumen
y/o la intensidad de entrenamiento con la intencin de
mejorar el rendimiento. Las mejoras se cree que podran
obtenerse comenzando un efecto rebote donde una
disminucin inicial en la estimulacin anabolizante hace que el
cuerpo supercompense aumentando significativamente la
acumulacin de protenas corporales (42.189). Se ha
demostrado que el estado de entrenamiento del individuo
afecta a la respuesta de sobrecarga, con una reduccin de los
efectos perjudiciales para el sistema endocrino visto en los que
tienen ms de un ao de experiencia (44). Para asegurar una
ptima supercompensacin, el perodo de sobrecarga debe ser
seguido por un descanso breve o cese de entrenamiento (99).
Los perodos prolongados sobrecarga, sin embargo,
pueden
conducir
rpidamente
a
un
estado
de
sobreentrenamiento (62). El sobreentrenamiento tiene efectos
catablicos en el tejido muscular, y se caracteriza por la
disminucin crnica de las concentraciones de testosterona y
hormonas luteinizantes, y un aumento de los niveles de
cortisol (43, 58, 140). Los estados de sobreentrenamiento que
causan en primer lugar el sndrome de sobreentrenamiento son
consecuencia de un trauma repetitivo sobre el sistema
musculoesqueltico resultante de la alta intensidad y el alto
volumen de entrenamiento (159,160). Sin embargo, los
estudios parecen mostrar que el sobreentrenamiento es ms el
resultado de un volumen excesivo que de intensidad (43,59).
Teniendo en cuenta que las capacidades recuperativas son
altamente variables entre los individuos, es esencial ser
consciente del nivel de entrenamiento de un atleta y ajustar el
volumen en consecuencia para evitar un efecto negativo sobre
la acumulacin de protenas.
Por otra parte, la bsqueda de entrenar con un alto
volumen debe equilibrarse con reducciones en el rendimiento
derivadas de largas sesiones de ejercicio. Entrenamientos largos
tienden a estar asociados con la reduccin de la intensidad del
esfuerzo, motivacin disminuida y alteraciones en la respuesta
inmune (92). En consecuencia, se ha propuesto que los
entrenamientos intensos no deberan durar ms de una hora
para asegurar la mxima capacidad de entrenamiento a lo
largo de la sesin (205).
La seleccin de ejercicios
Es un principio fsico muy aceptado que la variacin de los
parmetros del ejercicio (es decir, el ngulo de traccin, la
posicin de las extremidades, etc) pueden causar diferentes
patrones de activacin dentro de los compartimentos

musculares, y hacer a los msculos sinergistas ms o menos
activos (17). Esto es particularmente importante en un
protocolo orientado hacia la hipertrofia, donde promover el
crecimiento uniforme del tejido muscular es esencial para
maximizar la seccin muscular en general.
Los msculos pueden tener diferentes sitios de unin que
proporcionan una mayor influencia para la variacin de
acciones. El trapecio, por ejemplo, se subdivide de tal manera
que la regin superior eleva la escpula, las fibras medias
aducen la escpula y las inferiores deprimen la escpula (103).
Con respecto al pectoral mayor, la cabeza esternal es
significativamente ms activa que la cabeza clavicular en el
press de banca declinado (46). Adems, la cabeza clavicular del
pectoral mayor y la cabeza larga del trceps han demostrado
estar ms activas en el press de banca con agarre estrecho
frente a la variacin de agarre ancho, con aumento de la
actividad de deltoides anterior, en relacin con el aumento del
grado de inclinacin del tronco (14).
Las diferencias regionales dentro de varios msculos
pueden afectar a su respuesta a la eleccin del ejercicio. Por
ejemplo, las unidades motoras (MUs) lentas y rpidas a
menudo se distribuyen en conjunto por todo msculo, de
manera que una fibra de contraccin lenta puede ser activada
mientras una fibra de contraccin rpida situada a su lado
puede estar inactiva, y viceversa (7). Adems, los msculos
estn a veces divididos en componentes regiones
neuromusculares distintas, cada una de las cuales est inervada
por ramas del nervio correspondiente, lo que sugiere que las
distintas partes de un msculo pueden ser activadas o no en
funcin de la actividad (7). Por ejemplo, el sartorio, recto
interno del muslo, bceps femoral y semitendinoso estn todos
divididos en una o ms bandas fibrosas o inserciones, cada una
de las cuales est inervada por ramas nerviosas separadas (193,
198). Adems, el grcil y el sartorio se componen de fibras
relativamente
cortas,
en
serie
que
terminan
intrafascicularmente, refutando la suposicin de que las fibras
musculares se extienden siempre en su totalidad desde el
origen a la insercin (67).
Los efectos de la separacin muscular en la actividad
mecnica se observan en el bceps braquial, donde tanto la
cabeza larga como la corta tienen compartimientos
arquitectnicos que estn inervados por ramas privadas de las
neuronas primarias (151). Estudios que investigaron la actividad
muscular de la porcin larga del bceps braquial mostraron que
las MUs de la zona lateral son reclutadas para la flexin del
codo, las MUs en la zona medial son reclutadas para la
supinacin, y la MUs de la zona cntrica (entre medial y
lateral) se reclutan para combinaciones de flexin y supinacin
(175, 176, 184). Adems, la cabeza corta parece estar ms
activa en la segunda parte del curl de bceps (es decir, con una
mayor flexin del codo), mientras que la cabeza larga lo est
en la fase inicial (21).
Estas variaciones arquitectnicas del msculo dan apoyo a
la necesidad de adoptar un enfoque multiplanar y multiangular
al entrenamiento de hipertrofia usando una variedad de
ejercicios diferentes. Adems, dada la necesidad de estimular
completamente todas las fibras de un msculo, parecera que
una variacin de ejercicios frecuente est justificada para
maximizar la respuesta hipertrfica.
Hay evidencias que apoyan la inclusin de ejercicios
multiarticulares y uniarticulares de manera conjunta en una
rutina especfica de hipertrofia. Los ejercicios multiarticulares
reclutan grandes cantidades de masa muscular para llevar a
cabo el trabajo. Esto tiene un impacto en la respuesta
anablica hormonal al ejercicio. Especficamente, se ha
demostrado que la magnitud de las elevaciones hormonales
post-ejercicio est relacionada con la cantidad de masa
muscular implicada, con movimientos mulitarticulares que
producen grandes aumentos en los niveles de testosterona y
los niveles de GH en comparacin con ejercicios

monoartiuclares (64,91).
Por otra parte, los movimientos multiarticulares tienden a
requerir una significativa estabilizacin de todo el cuerpo, lo
que pone a trabajar numerosos msculos que de otro modo
no podran ser estimulados en movimientos monoarticulares.
La sentadilla, por ejemplo, dinmicamente recluta no slo el
cudriceps femoral y extensores de cadera, sino tambin la
mayora de los msculos del miembro inferior incluyendo los
aductores de la cadera, abductores de cadera y trceps sural
(132). Adems, se requiere una significativa actividad
isomtrica de una amplia gama de msculos de soporte
(incluyendo los abdominales, erector de la columna, trapecio,
romboides, y muchos otros) para facilitar la estabilizacin
postural del tronco. En total, se estima que ms de 200
msculos se activan durante la realizacin de la sentadilla
sentadilla (167). Para lograr un grado destacable de aspecto
musculoso, se requerira la ejecucin de decenas de
movimientos monoarticulares , una estrategia que es
ineficiente y poco prctica.
Por otra parte, los ejercicios monoarticulares permiten una
mayor concentracin en los msculos individuales en
comparacin con los movimientos multiarticulares. Durante la
ejecucin de movimientos multiarticulares, los principales
msculos motores pueden tener prioridad sobre los dems,
creando un desequilibrio hipertrfico entre msculos. El uso de
ejercicios monoarticulares de forma selectiva puede mejorar
los msculos subdesarrollados, para la mejora de la simetra
muscular. Adems, la arquitectura nica de los msculos
individuales sugiere que emplear ejercicios monoarticulares
puede provocar diferentes patrones de activacin
neuromuscular que aumentan el desarrollo muscular en
general (7).
El uso de superficies inestables en una rutina orientada a la
hipertrofia no es apoyado por la investigacin. Los ejercicios
de resistencia sobre una superficie inestable requieren la
activacin de una amplia la musculatura central para llevar a
cabo su realizacin (6, 110). Esto, a su vez, da lugar a una
disminucin significativa en la produccin de fuerza en los
principales msculos motores. Anderson y Behm (5)
encontraron que la produccin de fuerza fue un 59,6% menor
al realizar un press de pecho sobre una superficie inestable que
frente a una superficie estable. De manera similar, McBride et
al. (112) demostraron reducciones significativas de fuerza
mxima y velocidad de desarrollo de la fuerza (un 45,6 y
40,5%, respectivamente), al realizar una sentadilla en una
superficie inestable frente a una superficie estable. Estas grandes
reducciones en la produccin de fuerza disminuyen la tensin
dinmica de los msculos en cuestin, mitigando la respuesta
hipertrfica.
Una excepcin a la utilizacin de superficies inestables en
rutinas orientadas a la hipertrofia rutina orientada consiste en
ejercicios para la musculatura central. Sternlicht et al. (164)
encontraron que los crunchs abdominales en un fitball
provocaba una mayor actividad muscular, tanto en la parte
superior como inferior del recto abdominal que los crunchs
realizados bajo condiciones estables. Resultados similares
fueron mostrados por Vera-Garca et al. (186), que mostr el
aumento significativo de la actividad, tanto del recto
abdominal como de los oblicuos externos al realizar
enrollamientos abdominales (Crunch inverso) sobre una
superficie inestable en comparacin con una superficie estable.
Estos resultados sugieren un rol importante de las superficies
inestables en el desarrollo de los abdominales.
Intervalo de descanso
El tiempo transcurrido entre series se conoce como intervalo
de descanso. Los intervalos de descanso se pueden clasificar en
tres grandes categoras: corto (30 segundos o menos),

moderado o medio (60-90 segundos) y largo (3 minutos o
ms). El uso de cada una de estas categoras tiene distintos
efectos sobre la capacidad de resistencia y la acumulacin de
metabolitos, lo que afecta a la respuesta hipertrfica (195).
Los intervalos cortos de descanso tienden a generar un
estrs metablico significativo, aumentando as los procesos
anablicos asociados con la acumulacin de metabolitos (52).
Sin embargo, limitar el descanso a 30 segundos o menos no
permite el tiempo suficiente para un atleta para recuperar la
fuerza muscular, alterando significativamente el rendimiento
muscular en series o ejercicio posteriores (137,141). Por lo
tanto, los beneficios hipertrficos asociados a un mayor estrs
metablico son aparentemente contrarrestados por la
disminucin en la capacidad de la fuerza, haciendo que
intervalos cortos de descanso no sean ptimos para maximizar
las ganancias hipertrficas.
Los largos intervalos de descanso permiten la recuperacin
total de la fuerza entre series, facilitando la capacidad de
entrenar con la mxima capacidad de fuerza (121). de Salles et
al. (32) mostraron que los intervalos de descanso de 3-5
minutos permitieron realizar mayor nmero de repeticiones en
un entrenamiento multiserie con cargas de entre 50 y 90% de
1RM. Sin embargo, aunque la tensin mecnica se maximiza
con largos perodos de descanso, el estrs metablico queda
comprometido (92,94). Esto puede retrasar y disminuir el
impulso anablico, atenuando una mxima respuesta
hipertrfica.
Los intervalos de descanso moderados parecen
proporcionar un compromiso satisfactorio entre los periodos
de descanso largos y cortos para maximizar la hipertrofia
muscular. La investigacin indica que la mayor parte de la
capacidad de resistencia de un atleta se recupera en el primer
minuto despus del cese de la serie (168). Por otra parte, un
entrenamiento consistente con intervalos de descanso ms
cortos conduce a adaptaciones que permiten a un levantador,
en ltima instancia, sostener un significativamente mayor
porcentaje medio de 1RM durante el entrenamiento (95).
Estas adaptaciones incluyen el aumento capilar y densidad
mitocondrial y una mayor capacidad para amortiguar H+ y
lanzarlo fuera de msculo, minimizando as los descensos en el
rendimiento.
Los intervalos moderados de descanso tambin ayudan a
mejorar y prolongar el estado anablico del cuerpo en un
mayor grado que intervalos largos. Por un lado, descansos
moderados inducen una mayor hipoxia, elevando el potencial
para aumentar el crecimiento muscular (182). Los intervalos
moderados de descanso tambin se asocian con una mayor
acumulacin metablica, mediando un gran pico en las
concentraciones hormonales anablicas despus del ejercicio
(94). Sin embargo, hay algunas evidencias de que esta ventaja
hormonal no se mantiene durante mucho tiempo. Buresh et al.
(22) compararon la respuesta hormonal anablica en rutinas
con intervalos de descanso de 1 frente a 2,5 minutos. Aunque
los intervalos de descanso ms cortos tuvieron un mayor
impacto en la elevacin de los niveles de GH en las primeras
etapas de la protocolo, la diferencia en la respuesta hormonal
no fue significativa entre las rutinas al final de la quinta semana
y era inexistente en la semana 10. Esto sugiere una respuesta
post-adaptativa de los msculos a intervalos reducidos de
descanso, apoyando as la necesidad de periodizacin en un
programa de entrenamiento de resistencia destinado a la
hipertrofia.
El fallo muscular
El fallo muscular puede ser definido como el punto de una
serie a partir del cual los msculos ya no pueden producir la
fuerza necesaria para levantar concntricamente una carga
dada. A pesar de que los beneficios del entrenamiento al fallo
muscular son an materia de debate, lo que comnmente se
cree es que este tipo de entrenamientos es necesario para

maximizar la respuesta hipertrfica (196). Varias teoras han
sido propuestas para apoyo de esta afirmacin.
Por un lado, existe la hiptesis de que el entrenamiento al
fallo muscular activa un mayor nmero de MUs (196). Cuando
un levantador se fatiga, un nmero cada vez mayor de MUs
son reclutadas para continuar la actividad, proporcionando un
estmulo adicional para la hipertrofia (145). De este modo, el
fallo muscular parece proporcionar un estmulo al umbral de
las MUs cuando se utilizan rangos de repeticiones medias.
Entrenar al fallo tambin puede mejorar el estrs
metablico inducido por el ejercicio, potenciando as una
respuesta hipertrfica. Continuar entrenando en condiciones
de gluclisis anaerobica aumenta la acumulacin de
metabolitos, los que a su vez mejora el entorno hormonal
anablico. Linnamo et al. (104) mostraron que la realizacin
de series de 10RM al fallo provocaban una mayor elevacin en
la secrecin de GH postejercicio en comparacin con la misma
carga no llevada al fallo muscular.
Aunque el entrenamiento al fallo parece conferir
beneficios hipertrficos, existen evidencias de que tambin
aumenta la posibilidad de sobreentrenamiento y agotamiento
psicolgico (43). Izquierdo et al. (76) encontraron que el
entrenamiento al fallo causaba reducciones en reposo de las
concentraciones de IGF-1 y un descenso de los niveles de
testosterona durante el descanso a lo largo de un protocolo de
16 semanas, lo que sugiere que los sujetos podran haber
alcanzado el sobreentrenamiento. As, aunque parece prudente
incluir series realizadas al fallo en un programa orientado a la
hipertrofia, su uso debe ser periodizado y/o limitado para
evitar un estado de sobreentrenamiento.
La velocidad de la repeticin
La velocidad con la que un levantador realiza repeticiones
puede tener impacto en la respuesta hipertrfica. A pesar de
las limitaciones en la cantidad de investigaciones y los aspectos
de diseo del estudio, algunas conclusiones se pueden sacar
sobre el tema.
Con respecto a las repeticiones concntricas, hay algunas
evidencias de que las repeticiones rpidas beneficiosas para la
hipertrofia. Nogueira et al. (133) encontraron que la
realizacin de acciones concntrica de 1 segundo de cadencia
en lugar de tres segundos tena mayor impacto en el espesor
de musculatura de los miembros superior e inferior en hombres
de edad avanzada. Esto se puede atribuirse a un aumento del
reclutamiento y a la fatiga correspondiente al umbral de las
MUs. Otros estudios, sin embargo, sugieren que el
entrenamiento a velocidades moderadas tiene un efecto mayor
sobre la hipertrofia (56), tal vez a travs de una demanda
metablica aumentada (12). El mantenimiento de la tensin
muscular continua a velocidades de repeticin moderadas
tambin Se ha demostrado que mejora la isquemia muscular y
la hipoxia, aumentando as la respuesta hipertrfica (174).
Entrenar a velocidades muy lentas (es decir, entrenamiento
superlento) ha demostrado ser menos ptimo para el
desarrollo de fuerza e hipertrofia (82, 129), y por lo tanto
debera emplearse cuando el objetivo es maximizar el
crecimiento muscular.
Desde un punto de vista de la hipertrofia, la velocidad del
movimiento puede tener mayor importancia en el
componente excntrico de una repeticin. Aunque se ha
demostrado que las contracciones concntricas e isomtricas
producen una respuesta hipertrfica, la mayora de los estudios
parecen mostrar que las acciones excntricas provocan el
mayor efecto en el desarrollo muscular. Especficamente, el
entrenamiento excntrico se asocia con un aumento ms
rpido en la sntesis de protenas (122) y mayores aumentos en
la expresin del ARNm y IGF-1 (152) en comparacin con el
ejercicio concntrico. Por otra parte, el entrenamiento

isotnico e isocintico que no incluyen contracciones
excntricas resulta en una menor hipertrofia que los que s las
incluyen (39, 68, 74).
La superioridad hipertrfica del ejercicio excntrico es en
gran medida atribuida a una mayor tensin muscular bajo
carga. Se ha teorizado que esto es debido a una inversin del
principio de tamao de la contratacin, lo que resulta en que
fibras de contraccin rpida son selectivamente reclutadas
(152.173). Esto fue demostrado por Nardone y Schieppati
(128), quienes mostraron un desreclutamiento del msculo
sleo, de contraccin lenta, y un correspondiente aumento en
la actividad del gastrocnemio durante la flexin plantar
excntrica. Tambin hay pruebas de que las contracciones
excntricas dan lugar a la contratacin adicional de MUs
previamente inactivas (116, 127).
Como resultado de la tensin excesiva en un pequeo
nmero de fibras activas, el ejercicio excntrico tambin se
asocia con un mayor dao muscular en comparacin con
contracciones concntricas e isomtricas (116). Esto se
manifiesta como transmisin de la lnea Z, lo cual, ante la
investigacin actual, sugiere indicar una remodelacin
miofibrilar (30, 204). Se ha demostrado que la expresin
ARNm MyoD est especficamente regulada al alza por
cotracciones excntricas (78).
Shepstone et al. (152) encontraron que contracciones
excntricas rpidas (3,66 rads-1) resultaron significativamente
mejores para una mayor hipertrofia de fibras tipo II, en
comparacin con repeticiones excntricas lentas (0,35 rads-1).
Esto se sostiene gracias a la parte excntrica de la curva
fuerza-velocidad, que muestra que mayores fuerzas musculares
son generadas a velocidades ms altas. Sin embargo, los
hallazgos de este estudio son limitados ya que los sujetos
fueron entrenados en un dinammetro isocintico, que
proporciona una fuerza de resistencia contra el msculo
agonista y no es dependiente de la accin de la gravedad. El
entrenamiento dinmico constante tradicional de resistencia (es
decir, pesos libres, poleas, etc) no confieren una ventaja. Ms
bien, las contracciones excntricas son ayudadas por el la
accin de la fuerza gravitacional, lo que requiere que el
levantador resista la gravedad para mantener la tensin
muscular. Por lo tanto, una velocidad ms lenta de
movimiento ser necesaria para maximizar la respuesta al
entrenamiento (45).
APLICACIONES PRCTICAS
La investigacin actual sugiere que las ganancias mximas en la
hipertrofia muscular se consiguen mediante regmenes de
entrenamiento que producen estrs metablico importante
manteniendo al mismo tiempo un moderado grado de tensin
muscular. Un programa orientado a la hipertrofia debe
emplear un rango de 6-12 repeticiones por serie con intervalos
de descanso de 60-90 segundos entre series. Los ejercicios
deben variar de un modo multiplanar y multiangulat para
asegurar la estimulacin mxima de todas las fibras musculares.
Se deben realizar varias series en el contexto de una rutina
dividida de entrenamiento para aumentar el entorno
anablico. Al menos algunas de las series deben llevarse hasta
el punto de fallo muscular concntrico, quizs alternando
microciclos de series hasta el fallo con los que no se realizan al
fallo para minimizar el riesgo de sobreentrenamiento. Las
repeticiones concntricas se deben realizar a velocidades
rpidas o moderadas (1-3 segundos), mientras que las
excntricas deben realizarse a velocidades ligeramente ms
lentas (2-4 segundos). El entrenamiento debe ser periodizado
para que la fase de hipertrofia culmine en un breve periodo de
un mayor volumen de sobrecarga seguido de una puesta a
punto para permitir la ptima supercompensacin del tejido
muscular.

The Mechanisms of Muscle Hypertrophy Schoenfeld

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The Mechanisms of Muscle Hypertrophy Schoenfeld

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BRIEF REVIEW

THE MECHANISMS OF MUSCLE HYPERTROPHY AND

KEY WORDS muscle development, hypertrophic response,

he quest to increase lean body mass is widely

Address correspondence to Brad Schoenfeld, brad@workout911.com.

implications to a variety of populations associated with sports

TYPES OF MUSCLE HYPERTROPHY

Mechanisms of Muscle Hypertrophy

lacking and, if it does occur at all, the overall effects on muscle

SATELLITE CELLS AND MUSCLE HYPERTROPHY

Journal of Strength and Conditioning Research

Journal of Strength and Conditioning Research

The Akt/mTOR pathway is believed to act as a master

Mitogen-activated protein kinase is considered a master

Various Ca2+-dependent pathways have been implicated in

HORMONES AND CYTOKINES

proteolysis rather than heightening protein synthesis. Insulin

Insulin-like growth factor is often referred to as the most

Mechanisms of Muscle Hypertrophy

correlations between training-induced elevations in testosterone

Testosterone is a cholesterol-derived hormone that has a

Growth hormone is a polypeptide hormone considered to

Journal of Strength and Conditioning Research

Journal of Strength and Conditioning Research

occlusion significantly attenuated muscular atrophy in

INITIATION OF EXERCISE-INDUCED MUSCLE

Mechanisms of Muscle Hypertrophy

Exercise training can result in localized damage to muscle

This deforms membranes, particularly T-tubules, leading to

TRAINING VARIABLES AND MUSCLE HYPERTROPHY

Journal of Strength and Conditioning Research

Journal of Strength and Conditioning Research

Intensity (i.e., load) has been shown to have a significant

Training in a moderate repetition range also maximizes

A set can be defined as the number of repetitions performed

Mechanisms of Muscle Hypertrophy

highly variable between individuals, it is essential to be

It is a well-accepted fitness tenet that varying exercise

Journal of Strength and Conditioning Research

Journal of Strength and Conditioning Research

The time taken between sets is referred to as the rest interval.

Mechanisms of Muscle Hypertrophy

Muscular failure can be defined as the point during a set when

The speed with which a lifter performs repetitions can impact

quantity of research and aspects of study design, some

Journal of Strength and Conditioning Research

Journal of Strength and Conditioning Research

7. Antonio, J. Nonuniform response of skeletal muscle to heavy

The author would like to thank Dr. William Kraemer, Dr.

19. Brahm, H, Pehl-Aulin, K, Saltin, B, and Ljunghall, S. Net fluxes over

Mechanisms of Muscle Hypertrophy

47. Goldberg, AL, Etlinger, JD, Goldspink, DF, and Jablecki, C.

56. Hakkinen, K, Komi, PV, and Alen, M. Effect of explosive type

57. Hakkinen, K and Pakarinen, A. Acute hormonal responses to two

37. Essen-Gustavsson, B and Tesch, PA. Glycogen and triglyceride

58. Hakkinen, K and Pakarinen, A. Serum hormones in male strength

38. Evans, WJ. Effects of exercise on senescent muscle. Clin Orthopaed

59. Hakkinen, KA, Pakarinen, A, Alen, M, Kauhanen, H, and Komi, PV.

Journal of Strength and Conditioning Research

Journal of Strength and Conditioning Research

85. Kerksick, CM, Rasmussen, CJ, Lancaster, SL, Magu, B, Smith, P,

86. Kerksick, CM, Wilborn, CD, Campbell, BI, Roberts, MD,

71. Holm, L, Reitelseder, S, Pedersen, TG, Doessing, S, Petersen, SG,

88. Kramer, HF and Goodyear, LJ. Exercise, MAPK, and NF-kappaB