REVIEW

URRENT
C
OPINION

Amino acid sensing and activation of mechanistic

target of rapamycin complex 1: implications for
skeletal muscle
Daniel J. Ham, Gordon S. Lynch, and Rene Koopman

Purpose of review
This article evaluates recent studies on the mechanisms involved in sensing changes in amino acid
availability and activation of the mechanistic target of rapamycin complex 1 (mTORC1).
Recent findings
mTORC1 is sensitive to changes in amino acid availability and a well known regulator of protein turnover.
The mechanisms of amino acid sensing and mTORC1 signaling are emerging with multiple potential
sensors (e.g., solute carrier family 38, member 9, lysosomal protein transmembrane 4 beta/solute carrier
family 7, member 5-solute carrier family 3, member 2) and signal transducers (e.g., Sestrins, ADPribosylation factor 1, and microspherule protein 1) identified. Studies in various cell lines have unveiled the
importance of the lysosome in amino acid sensing and signal transmission.
Summary
Recent discoveries in amino acid sensing highlight a complex scenario, whereby mTORC1 is not merely
sensitive to some amino acids and not others, but where specific amino acids are sensed by specific
pathways under specific conditions. The physiological purpose of such an arrangement remains to be
unraveled, but it would allow mTORC1 to precisely regulate growth during different metabolic conditions.
Understanding the mechanisms responsible for sensing amino acid availability and regulating mTORC1
activity is an important prerequisite for the development of nutritional strategies to combat skeletal muscle
wasting disorders.
Keywords
amino acid metabolism, lysosome, protein synthesis

INTRODUCTION
As early as 1975, it was clear that not all amino acids
had a similar capacity to regulate protein metabolism. In a landmark study, Buse and Reid [1] discovered that unlike other amino acids, the essential
branched-chain amino acid leucine rapidly stimulated muscle protein synthesis and reduced protein
breakdown in skeletal muscle in vitro. Since then a
multitude of studies in cells, animals, and humans
have demonstrated a potent stimulation of protein
synthesis by essential amino acids, particularly leucine (for reviews see [2,3]). Although the signaling
proteins that regulate protein metabolism are extensive, the mechanistic target of rapamycin complex 1
(mTORC1) has emerged as a central regulator that
integrates signals from nutrients (e.g., amino acids),
growth factors (e.g., insulin), energy status (ATP),
and stress (e.g., oxidative stress) [4,5]. Growth factors lead to mTORC1 activation by a well defined
mechanism involving the phosphorylation and

inhibition of two key suppressors of mTORC1 activation, tuberous sclerosis 2 (TSC2) and proline-rich
Akt substrate of 40 kDa [4]. However, growth factors
cannot effectively activate mTORC1 without the
presence of amino acids, which are both necessary
and sufficient to activate mTORC1 [5].
Modulating mTORC1 and protein metabolism
through amino acid supplementation has received
considerable attention as a potential treatment for
muscle wasting. However, despite an abundance of
amino acid supplementation studies, understanding the underlying mechanisms by which amino
Basic and Clinical Myology Laboratory, Department of Physiology, The
University of Melbourne, Victoria, Australia
Correspondence to Rene Koopman, PhD, Department of Physiology, The
University of Melbourne, VIC 3010, Australia. Tel: +61 3 8344 0243;
fax: +61 3 8344 5818; e-mail: rkoopman@unimelb.edu.au
Curr Opin Clin Nutr Metab Care 2016, 19:6773
DOI:10.1097/MCO.0000000000000240

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Protein, amino acid metabolism, and therapy

KEY POINTS
 mTORC1 is sensitive to changes in amino acid
availability and a well known regulator of
protein turnover.
 The mechanisms of amino acid sensing and mTORC1
signaling are emerging with multiple potential sensors
[e.g., solute carrier family 38, member 9 (SLC38A9),
lysosomal protein transmembrane 4 beta (LAPTM4b)/
solute carrier family 7, member 5-solute carrier family
3, member 2 (LAT1-4F2hc)] and signal transducers
[e.g., Sestrins, ADP-ribosylation factor 1 (ARF-1), and
MCRS1] identified.
 Studies in various (cancer) cell lines have unveiled the
importance of the lysosome in amino acid sensing and
signal transmission.
 Understanding the mechanisms responsible for sensing
amino acid availability and regulating mTORC1 activity
is an important prerequisite for the development of
nutritional strategies to combat skeletal muscle
wasting disorders.

acid availability is sensed by skeletal muscle cells to

regulate the mTORC1 network remains elusive. In
contrast, over the last 5 years, elegant mechanistic
studies in human embryonic kidney (HEK) cells,
mouse embryonic fibroblasts (MEF), and various
cancer cell lines have advanced our understanding
of how cellular amino acid sensing regulates
mTORC1 and controls cell growth. These mechanistic studies paint a complex picture regarding the
control of protein metabolism and cell growth by
amino acids. A better understanding of how amino
acid availability is sensed by cells will enhance our
interpretation of studies on amino acid supplementation relevant to nutrition and physiology.
The ever-expanding network of amino acidsensitive events upstream of mTORC1 continues
to expand and the mechanisms of amino acid
sensing appear specific for different amino acids.
Perhaps the most important advance in recent times
was the identification of the lysosomal amino acid
transporter SLC38A9 as the most promising amino
acid-sensor candidate [6 ,7 ]. In this review, we
specifically highlight how our understanding of
amino acid sensing has progressed over the last year
and discuss gaps in our current knowledge and
implications for future research in skeletal muscle.
&&

&&

Lysosomal localization is important for

mechanistic target of rapamycin complex 1
activation
Studies in many different cell lines (HEK, MEF, and
various cancer types) have revealed the importance
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of the lysosome in amino acid sensing and signal

transmission. Upon amino acid stimulation,
mTORC1 colocalizes with the lysosome, where it
interacts with key components of the amino acid
sensing machinery [e.g., vacuolar adenosine triphosphatase (v-ATPase), Rags, and the Ragulator]
along with the growth factor sensitive protein,
Rheb. The lysosome is the endpoint for many catabolic processes, such as autophagy, where it is
responsible for breaking down proteins and organelles into constituent amino acids. The lysosome is
an ideal storage site for amino acid sensing, providing access to an enriched source of amino acids
even during conditions of low extracellular amino
acid availability, through the catabolism of proteins
and organelles. As such, the lysosomal localization
of mTORC1 signaling is ideal for mTORC1 to assess
the metabolic state of the cell and orchestrate appropriate growth signals [8].
Amino acid sensitive signals converge upon
the Rag guanosine triphosphatase (GTPases),
which are anchored to the lysosomal surface by
the Ragulator complex [8]. Rags function as heterodimers with Ras-related GTP-binding protein
(Rag) A or RagB binding to RagC or RagD. Amino
acid stimulation activates the Rag complex by
modulating the guanine nucleotide-loading status
of the Rags. The active complex consists of RagA/B
in the GTP-bound state and RagC/D in the guanosine diphosphate (GDP)-bound state. The guanine nucleotide-loading status of Rags can be
regulated by multiple factors including: GTPaseactivating proteins (GAPs) that stimulate GTP
hydrolysis [e.g., GTPase-activating proteins toward
Rags 1 (GATOR1) complex [9]]; guanine nucleotide exchange factors that facilitate GDP dissociation (e.g., the Ragulator complex); and
nucleotide dissociation inhibitors [e.g., GDP-dissociation inhibitor (GDIs)] that prevent GDP dissociation, which until the recent discovery of the
actions of the Sestrin family of proteins, had not
been described for Rags. Upon activation, the Rag
complex promotes mTORC1 translocation to the
lysosome where it can interact with Rheb, resulting in activation of mTORC1 and its downstream
targets ribosomal protein S6 kinase 1, 70 kDa
(S6K1) and eukaryotic translation initiation factor
4E binding protein 1 (4EBP1) [2].
The lysosome is not only where mTORC1 interacts with Rheb to drive protein synthesis and cell
growth, but rather a key point of control for
mTORC1 activation and repression. The regulation
of Rags and their guanine nucleotide-loading
status has emerged as an important point of
control for sensing amino acid sufficiency and
insufficiency and promoting or repressing the
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Amino acid sensing Ham et al.

activity of mTORC1. It is important to note

that it is equally important that mTORC1 is
repressed during conditions of reduced amino
acid availability and activated during amino acid
repletion. For example, in RagAGTP/GTP knockin
mice where RagA is perpetually GTP-bound
(active), the mice are incapable of disabling
mTORC1 signaling and arresting growth processes
during amino acid deprivation. As a result, RagAGTP/
GTP
knockin mice have increased neonatal lethality
during the period of fasting between birth and
suckling [10].

Sestrins suppress mechanistic target of

rapamycin complex 1 activity during amino
acid insufficiency

Once amino acid sufficiency stimulates the translocation of mTORC1 to the lysosome, it can interact
with Rheb, which integrates signals from various
growth factors (e.g., insulin and insulin-like growth
factor 1), although the mechanisms responsible for
this interaction are unclear. Growth factors activate
Rheb, but cannot activate mTORC1 in the absence of
amino acids. A recent breakthrough identified microspherule protein 1 (MCRS1) as an amino acid sensitive molecular link between activated Rheb
and
mTORC1 [13 ]. MCRS1 interacts with both mTORC1
and Rheb independently. Interaction of MCRS1 with
mTORC1 is essential for mTORC1 activity, but is
insensitive to amino acids. On the other hand, interaction of MCRS1 with GTP-bound (activated) Rheb is
amino acid sensitive, with the MCRS1/Rheb interaction being reduced by amino acid depletion and
strongly enhanced by amino acid stimulation. The
interaction between MCRS1 and Rheb is essential for
the lysosomal localization of Rheb, but not mTORC1,
since MCRS1 suppression abolished the lysosomal
localization of Rheb but not mTORC1 [13 ]. Furthermore, in confirmation of the role of MCRS1 in linking
Rheb and mTORC1 at the lysosome, MCRS1
depletion impaired the Rheb/mTORC1 interaction
in multiple cell lines, whereas MCRS1 knockdown
experiments in mice resulted in severe mTORC1
activity inhibition [13 ].
&&

Recently, the Sestrin family of proteins have

emerged as important amino acid-sensitive regulators of mTORC1, potently suppressing its activity
during amino acid insufficiency [11 ,12 ]. The
critical importance of Sestrins in signaling amino
acid availability to mTORC1 was highlighted by
knockout studies in mice, where knockout of all
three Sestrins (13) was associated with ineffective
inactivation of mTORC1 signaling in skeletal
muscle, liver, and heart tissue during neonatal
fasting and dramatically reduced postnatal
survival [11 ]. Although it is well known that
the Sestrins regulate mTORC1 activity, the mechanisms responsible have remained elusive. Early
studies concluded that Sestrins act through TSC2
and AMP-dependent protein kinase to inhibit
mTORC1, but recent work [11 ] demonstrated
that neither protein was essential for the regulation of mTORC1 by Sestrin. Peng et al. [11 ] showed
that Sestrins can act as GDIs for Rags, locking
RagA/B in either the GTP or GDP-bound form,
thereby suppressing both activation and deactivation of mTORC1 in response to amino acid availability. In addition, an amino acid-sensitive
interaction has been reported between Sestrin2
and the GTPase-activating proteins toward Rags 2
(GATOR2) complex, a poorly understood positive
regulator of mTORC1, which may act upstream
or in parallel to the RagA/B GAP GATOR1 [12 ].
However, despite the requirement for both GATOR1
and Rags for the inhibition of mTORC1 signaling
by Sestrins, the interaction between GATOR2 and
GATOR1 was not disrupted nor was the GAP activity
of GATOR1 to RagA/B affected by Sestrins [12 ].
Further work is required to fully understand the
mechanisms responsible for the regulation of
mTORC1 by Sestrins, and the upstream mechanisms
responsible for its activation.
&&

Microspherule protein 1 facilitates

lysosomal localization and coupling
of Rheb to mechanistic target of
rapamycin complex 1

&

&&

&&

&&

&&

&&

&

&

Mechanistic target of rapamycin complex 1

represses extracellular protein utilization
during amino acid insufficiency
The Rags themselves can also play a role in the
inhibition of mTORC1. In RagC/D knockout cells
the repression of mTORC1 by amino acid deprivation is attenuated [14 ]. In fact, the Rags appear
to also play a role in recruiting TSC2 to the lysosomal membrane where it inhibits mTORC1 [15].
Further complicating the role of mTORC1 in amino
acid sensing and growth, Palm et al. [16 ] observed
an inhibitory effect of mTORC1 on cancer cell
proliferation when cells were forced to rely on
extracellular proteins as an amino acid source.
Although the lysosomal degradation of extracellular
proteins provided sufficient amino acids to promote
mTORC1 activation and sustain cell survival,
significant cell accumulation did not occur in the
absence of free amino acids. In fact, in the absence
of free amino acids, mTORC1 inhibition (using
Torin1 or rapamycin) increased the catabolism

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69

Protein, amino acid metabolism, and therapy

of extracellular proteins and enhanced cell

proliferation [16 ]. As such, by controlling the lysosomal degradation of extracellular proteins,
mTORC1 precisely matches cell growth with the
availability of free amino acids. Intuitively, it makes
sense that mTORC1 would inhibit cell growth when
the cell relies on the breakdown of extracellular
proteins to survive. Although the physiological role
of these processes in skeletal muscle is currently
unknown, the control of autophagy by mTORC1
is well documented in this tissue [17,18]. Autophagy
is tightly regulated in skeletal muscle, with both
excessive activation and inhibition resulting in atrophy [17]. Interestingly, it was demonstrated recently
in skeletal muscle cells that mTORC1 not only
regulates autophagy, but autophagy also regulates
mTORC1 and the amino acid signaling network
[19 ].
&&

&

Recently discovered intracellular amino acid

sensors
Despite the identification of many proteins
involved in signaling amino acid sufficiency to
mTORC1, the actual amino acid sensors have
largely remained elusive. Given the importance of
the lysosome in amino acid signaling and the
requirement for amino acids in the lysosomal
lumen, it would be logical for an amino acid sensor
to have a lysosomal transmembrane domain and
interact with known components of the amino
acid sensing pathway. This premise led to the discovery of SLC38A9, a member of the solute carrier
38 family which, unlike other solute carrier
proteins, colocalizes with both lysosomal markers
(e.g., lysosomal-associated membrane protein 1
and CD63) and key components of the amino acid
sensing pathway, including Ragulator, RagA
and C, and the v-ATPase [6 ,7 ]. SLC38A9 overexpression renders mTORC1 resistant to amino acid
starvation, whereas silencing blunts amino acidinduced mTORC1 activation [6 ,7 ]. The N-terminal interacts with the RagulatorRag GTPase complex, which is the key step required for mTORC1
activation, but requires the transmembrane domain
to confer amino acid responsiveness [7 ]. Although
SLC38A9 is capable of bidirectional amino acid transport, this does not appear to be its primary purpose,
since the measured rates of glutamine influx and
efflux are moderate compared with other lysosomal
amino acid transporters [6 ,7 ]. Thus, SLC38A9
could be considered a transporter that also acts as a
receptor, or a transceptor, with properties similar to
those of the amino acid sensors GAP1 and yeast
extracellular amino acid sensor described in yeast
and Drosophila [6 ].
&&

&&

&&

&&

&&

&&

&&

&&

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Intriguingly, SLC38A9 has a particular penchant

for arginine. Recent experiments revealed knockout
of SLC38A9 strongly inhibited arginine-induced
mTORC1 activation but cells remained sensitive
to leucine [7 ]. Furthermore, SLC38A9 is capable
of bidirectional transport of [3H]arginine and
[3H]asparagine, but not [3H]leucine or [3H]histidine.
As such, SLC38A9 appears to play a central role in
sensing and relaying arginine but not leucine levels
to mTORC1. Of course, SLC38A9 is one of many
amino acid sensors, since amino acid-sensitive
events have been reported upstream of folliculin
[20,21] and GATOR1 [12 ] and in response to other
amino acids such as glutamine and leucine.
Another important question regarding amino
acid sensing at the lysosome, is how lysosomes
become enriched with amino acids to activate
mTORC1 during periods of high extracellular amino
acid availability. Recent findings suggest a mechanism involving the leucine transporter LAT1-4F2hc.
LAT1/4F2hc (or SLC7A5/SLC3A2) is a bidirectional
amino acid transporter that controls the simultaneous cellular efflux of glutamine/nonessential
amino acids and cellular influx of L-leucine/essential amino acids [22]. A new role has been identified
for this transporter in mediating the transport of
leucine into lysosomes for inside-out activation of
mTORC1 through the v-ATPase (Fig. 1). Upon
amino acid stimulation, LAT1-4F2hc is recruited
to the lysosome from the cell membrane and/or
the Golgi by LAPTM4b, where it commences bidirectional transport of leucine into the lysosome and
glutamine out of the lysosome, and is necessary for
mTORC1 activation [23 ]. Therefore, LAT1-4F2hc
plays an important role in transporting extracellular
leucine into the cytosol and then transporting cytosolic leucine into the lysosome. As such, for activation of mTORC1 by lysosomal leucine, substantial
extracellular and cytosolic leucine concentrations
along with sufficient cytosolic and lysosomal concentrations of neutral nonessential amino acids
(e.g., glutamine) would be required. The requirement for cytosolic and lysosomal nonessential
amino acids also implicates other transporters
capable of promoting nonessential amino acid
uptake, such as SNAT3 (SLC38A3) and SNAT5
(SLC38A5). For a review on the role of amino acid
transporters in amino acid sensing [24]. Although
the precise mechanisms responsible for leucine sensing remain to be determined, the discovery of
LAPTM4b-induced translocation of a functional leucine transporter to the lysosome is a major step
forward in our understanding of the inside-out
mechanism of mTORC1 activation by lysosomal
amino acids, originally described by Zoncu et al.
[25].
&&

&

&&

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Amino acid sensing Ham et al.

FIGURE 1. Key mechanisms in amino acid sensing and mTORC1 activation. Newly discovered players (in bold) include:
SLC38A9, described as a transceptor, which senses lysosomal arginine availability [6 ,7 ]; the sestrins, which repress
mTORC1 activity during amino acid insufficiency [15,16 ]; microspherule protein 1, which couples Rheb to mTORC1 in an
amino acid-sensitive fashion [13 ]; LAPTM4b, which facilitates the translocation of LAT1-4F2hc and influx of leucine into the
lysosome [27]; and ARF1, which mediates glutamine induced mTORC1 activation independently of the Rags [26 ]. mTORC1,
mechanistic target of rapamycin complex 1.
&&

&&

&&

&&

&&

Glutamine modulates mechanistic target of

rapamycin complex 1 independent of the
Ragulator complex
The particular sensitivity of mTORC1 to some
amino acids, the most notable being leucine,
arginine, and glutamine, has been known for some
time but all were thought to act through changes in
Rag GTPase loading at the lysosomal surface. However, a recent study casted significant doubt on this
assertion. Interestingly, in Rag A/B knockout cells,
amino acid sensitivity was only partially impeded
compared with control cells [26 ]. By stimulating
Rag A/B knockout cells with each of the standard
20 amino acids, Jewell et al. [26 ] determined that
mTORC1 activation by both leucine and arginine
was abolished, but glutamine-induced activation
of mTORC1 was unperturbed. Although glutamine
still required a functional v-ATPase, the Ragulator
complex was not essential for mTORC1 activation.
Instead, the ARF1 GTPase mediated the translocation of mTORC1 to the lysosome in glutamine-stimulated Rag A/B knockout cells [26 ].
&&

&&

&&

In an effort to transition some of the excellent

progress made toward understanding amino acid
sensing in more physiological contexts, Averous
et al. [14 ] investigated the effect of amino acid or
leucine deprivation and stimulation on lysosomal
localization and mTORC1 activity in MEF cells with
or without serum. Evidence of amino acid specific
control of mTORC1 was also observed, but in contrast to Jewell et al. [26 ] this group observed modulation of mTORC1 activity but not lysosomal
localization by leucine. Leucine deprivation and
then leucine stimulation first blunted and then
restored mTORC1 activity based on the phosphorylation status of S6K1 and 4EBP1, without affecting
the lysosomal localization of mTORC1. Furthermore, in RagC/D knockdown cells, mTORC1
activity remained sensitive to leucine availability
without localization to the lysosome [14 ].
Together, these results highlight that control of
mTORC1 activity is highly context dependent and
amino acid specific, and mTORC1 maintains amino
acid sensitivity in the absence of Rag GTPases

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&

&&

&

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71

Protein, amino acid metabolism, and therapy

&

&&

&

[14 ,26 ] and, at least in MEF cells [14 ], independent of lysosomal localization.

Acknowledgements
None.

Translating amino acid sensing mechanisms

to skeletal muscle

Financial support and sponsorship

D.H. is supported by a Research Fellowship from the
European Society for Clinical Nutrition and Metabolism
(ESPEN).

It is important to note that amino acid sensing

may vary widely between different tissues and cell
lines [27]. Although some studies have demonstrated skeletal muscle effects of amino acid
sensitive proteins (e.g., the Sestrins [11 ]), the
majority of our understanding of amino acid
sensing comes from mechanistic studies in HEK,
MEF, and cancer cell lines and may not reflect
sensing mechanisms in skeletal muscle. Some
progress has been made in applying some of these
findings to skeletal muscle. For example, increases
in RagB mRNA and protein in response to
increased amino acid availability have been
observed in human skeletal muscle [28 ]. Sensitivity of mTORC1 to arginine was also recently
demonstrated in a mouse skeletal muscle cell line
[29]. Although it has been known for many years
that leucine is a potent acute modulator of protein
metabolism in human skeletal muscle, chronic
leucine supplementation studies failed to demonstrate changes in skeletal muscle mass or strength
during muscle wasting conditions [2]. Furthermore, under many catabolic conditions, skeletal
muscle becomes insensitive to changes in amino
acid availability, an observation termed anabolic
resistance [30]. Further work is needed to increase
our understanding of the mechanisms involved
in amino acid sensing and their regulation of
muscle mass during health and disease. This
knowledge is essential for the development of
efficacious nutritional interventions for skeletal
muscle wasting disorders.
&&

&

CONCLUSION
Recent discoveries on the mechanisms of amino
acid signaling highlights the complexity of amino
acid sensing, whereby mTORC1 is not merely
sensitive to some amino acids and not others,
but where specific amino acids are sensed in
specific ways. The physiological purpose of such
an arrangement remains to be unraveled, but it
would allow mTORC1 to precisely regulate growth
during different metabolic conditions. A greater
understanding of the mechanisms responsible for
amino acid sensing, and their dysregulation
during skeletal muscle diseases and disorders, is
an important prerequisite for the development of
optimal nutritional strategies to combat skeletal
muscle wasting.
72

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Conflicts of interest
There are no conflicts of interest.

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