Nutrition and Skeletal Muscle

Italy

Part I

General Aspects: Skeletal Muscle Physiology and Nutrition

Outline

Chapter 1 Skeletal Muscle Mass Indices in Healthy Adults

Chapter 2 Reduced Skeletal Muscle Mass and Lifestyle

Chapter 3 Molecular Mechanisms of Postmeal Regulation of Muscle Anabolism

Chapter 4 Adaptation of Skeletal Muscle Mass and Metabolism to Physical Exercise

Chapter 1

Skeletal Muscle Mass Indices in Healthy Adults

Heliodoro Alemán-Mateo¹ and Roxana E. Ruiz Valenzuela²,    ¹Departamento de Nutrición y Metabolismo, Coordinación de Nutrición, Centro de Investigación en Alimentación y Desarrollo (CIAD), A.C. Hermosillo, Sonora, México,    ²Departamento de Salud, Universidad Iberoamericana, Ciudad de México-Tijuana, Tijuana, Baja California, México

Abstract

Skeletal muscle (SM) is a key component of nutritional status and functionality. The adjustment of SM by height or other anthropometric parameters in young adults has generated several indices that serve as indicators of muscularity. These SM indices have been generated in distinct young adult populations around the world and are now the basis for diagnoses of sarcopenia. To our knowledge, 21 cutoff points based on SM exist for younger adult populations worldwide; specifically, 17 dual-energy X-ray absorptiometry (DXA)-derived appendicular skeletal muscle mass indices, 3 DXA-derived total SM indices (TSMI), and one DXA-derived total lean body mass index. In addition, there are seven indices derived from bioelectrical impedance analysis, one magnetic resonance imaging-derived TSMI, and one that uses an ultrasound technique. In conclusion, SM indices should be applied to specific gender and ethnic populations to avoid variations in estimates of the prevalence of sarcopenia in older people.

Keywords

Body composition; total and appendicular skeletal muscle mass; skeletal muscle indices; sarcopenia; older people; young adult populations; dual-energy X-ray absorptiometry; bioelectrical impedance analysis

Introduction

Skeletal muscle (SM) increases during postnatal development through a process of hypertrophy of the individual muscle fibers; a similar process may be induced in adult SM in response to contractile activity like strength exercises, and to androgens and β-adrenergic agonists [1]. SM remains relatively constant during the third and fourth decades of life but begins to decline at ~45 years of age in both genders [2]. In other words, age exerts a strong influence on SM, but gender does as well [3–8]. Several studies have demonstrated the effects of age and gender on SM, and some have examined the effects on its distribution [2,5–6]. Perhaps the most relevant study on this issue was published by Janssen et al. [2], who used an in vivo method to study body composition using, particularly, magnetic resonance imaging (MRI) to provide precise and reliable measurements of SM and its distribution in a broad sample of Caucasian men and women. The results of this study reported new findings on the behavior of SM mass during the lifecycle in both men and women subjects.

Due to the growing awareness of the importance of SM on functionality and other clinical entities in older age groups [9–16], there is a need to establish reference values for relative SM in young adult populations using the most precise and accurate methods available, and considering the factors of age, gender, and ethnicity. It is important to stress that few countries have been able to conduct national-level studies of this kind [10,17–19]. Some published works based on small samples of healthy young adult subjects reported data on SM [2,6,20–21] and proposed cutoff points for diagnosing sarcopenia—i.e., low SM mass—and sarcopenia syndrome [9,10,17,22–42]. To our knowledge, 21 cutoff points based on SM exist; specifically, 17 dual-energy X-ray absorptiometry (DXA)-derived appendicular skeletal muscle mass (ASM) indices, 3 DXA-derived total SM (TSM) indices, and one DXA-derived total lean body mass (LBM) index for younger adult populations around the world [9,17,22–36], together with seven indices derived from bioelectrical impedance analysis (BIA) [10,37–42], one that used an ultrasound technique [43], and one MRI-derived TSM index (TSMI) [19]. Before presenting the main results of the published ASM, TSM, and LBM indices, we will first review the biological bases that underlie them.

The Biological Bases That Underlie the Indices

Indices are association measurements that can be very useful in classifying nutritional status or, as in the present case, the stadia of SM, evaluating the chronicity of the skeletal muscle loss and assessing the efficacy of nutrition on loss of SM during the intervention therapy. They may also serve to quantify various components of body mass. Indices of this kind are usually divided into (1) those relative to weight and height and (2) those relative to body composition. SM indices are the ones most closely related to body composition that are used to diagnose presarcopenia and sarcopenia syndrome in geriatric populations. As mentioned above, SM tissue is dependent on age, gender, body weight, height, and ethnicity [2,5–6]. It is important to note that much of our current understanding of SM is based on studies that used DXA and MRI, two in vivo methods for analyzing body composition [2,5–6] that can accurately measure total or regional SM. DXA- derived lean tissue in arms and legs or ASM account for >75% of total SM [44], which constitutes the primary portion of SM involved in ambulation, physical activities, and functionality across the lifespan.

To clarify the origin of an index, particularly ASM, we examined the main findings reported by Gallagher et al. [6], who assessed SM components by DXA in 148 healthy adult women (80 African-Americans, 68 Caucasians) and 136 healthy adult men (72 African-Americans, 64 Caucasians) with an age range of 21.1–67.5 years. First, they noted a significant negative correlation between ASM and age in all four groups. After adjusting for age, they determined that ASM was significantly and positively correlated with body weight and height in both ethnic groups, and in both men and women. Using multiple regression models, they then explored the independent effects of height, weight, age, gender, and ethnicity on ASM. In their predicted ASM model, height and weight explained 64% and 67%, respectively, of ASM variance in the African-American and Caucasian women, and 63% and 39%, respectively, in the African-American and Caucasian men. Smaller contributions were found for age. Interestingly, after adjusting for height, body weight, and age, an effect of gender was also found, as the men were found to have greater ASM than the women in both groups of subjects across the entire age range. Finally, a significant effect of ethnicity on ASM was found, as the African-American men and women had greater adjusted ASM than the Caucasian subjects [6].

Three years later, Janssen et al. [2] examined the influence of age, gender, body weight, and height on TSM assessed by whole body MRI in a large, heterogeneous sample of 468 men and women aged 18–88 years. It is important to mention that this study included two additional ethnic groups—Asians and Hispanics—in assessing TSM and its distribution [2]. As in the case of Gallagher et al. [6], these researchers also reported a significant effect of height, body weight, age, and gender on total and regional or appendicular SM. In another significant finding related to this chapter, Janssen et al. [2], demonstrated that the substantial increase in body weight observed between 18 and 40 years of age was not associated with a corresponding increase in TSM. Instead, the absolute quantity of TSM was maintained into the fifth decade of life, but with noticeable losses thereafter. This finding is important so as not to limit the cutoff points for SM mass indices for people aged 18–40 years, as was originally proposed in Rosseta’s study [6], and the body composition reference values from National Health and Nutrition Examination Survey [17] or Korean studies [29,33–34].

Numerous body composition indices have been generated by considering the biological and statistical associations among certain aspects of body composition with age, and specific anthropometric variables; especially, the strong correlation between absolute SM and height. Originally, in order to define low SM mass or sarcopenia, it was necessary to have a measure related to the amount of existing SM [9], and as previously mentioned, the absolute values of SM correlates strongly with height. Therefore, ASM (kg) divided by height squared (ht²) produces an index of relative appendicular SM mass that serves as an indicator of muscularity. In fact, Baumgartner et al. [9] established that placing ht² in the denominator constituted the best common power for minimizing the correlation of the index with height across all gender, ethnic and age groups, and study populations, since adjusting TSM or ASM for size eliminates the differences in the amount of SM associated with the greater height of young adults, as well as those related to gender and ethnicity. The resulting index permits better comparisons than absolute values of SM or any other parameter of body composition.

SM has also been adjusted by body weight following the same principle as adjustment by ht². Following Janssen et al. [10], SM adjusted by body weight considered adjustments for both stature and the mass of non-SM tissues (i.e., fat, organs, and bones) under the assumption that most mobility tasks and daily living activities are strongly influenced by body size. In older people, in addition to the adjustment by height, SM has also been adjusted by fat mass. Originally, it was hypothesized that SM adjusted by height and fat mass would better identify subjects with sarcopenia or with low SM than an index adjusted only for ht² and that individuals so identified as such might be at even greater risk for poor lower extremity functioning [45].

With respect to the adjustments of absolute SM values by ht², body weight, fat mass, or body mass index, a debate is ongoing as to which of these different indices is the best SM parameter and, therefore, the one that should be included in the criteria to define sarcopenia. Based on their results, Han et al. [42] proposed using absolute SM adjusted by height, because it correlated more closely with grip strength and with better muscular function than SM adjusted by body weight. Therefore, they recommended utilizing SM adjusted by height to diagnose sarcopenia syndrome.

To the best of our knowledge, no established cutoff points adequately identify the level at which relative SM becomes deficient or low SM. In the most recent international consensus on the operational definition of presarcopenia and sarcopenia syndrome by the European Working Group on Sarcopenia in Older People (EWGSOP) [46], the International Working Group on Sarcopenia (IWGS) [47], and the Asian Working Group for Sarcopenia (AWGS) [48], the cutoff values for each gender were redefined, respectively, as values one or two standard deviations (SD) below the gender-specific mean values of the reference data of a healthy young adult population [9–10,46–48]. The usefulness of these criteria and their corresponding cutoff points is based on a normal distribution which assumes that 68% of cases would fall within one standard deviation from the mean, and that 95% of all cases would fall within two standard deviations. As a result, the ASM index (ASMI) not only adjusts ASM according to height but also takes into account the lower correlation between height and ASM; this means, a deficit, expressing low appendicular SM mass or presarcopenia, or an excess, suggestive of high appendicular lean tissue or muscularity, expressed as high ASM. Finally, this criterion (−2 SD of the mean values of the gender–ethnic-specific SM indices from a young adult population) is the one most often used and associated with impaired physical performance and physical disability in geriatric populations [9–10].

Different Skeletal Muscle Indices Generated Worldwide

Currently, sarcopenia syndrome is characterized by low SM plus low muscle strength or low physical performance [46–48]. To establish low SM, some researchers and different international consensus on sarcopenia (EWGSOP, IWGS, AWGS) have considered some indices based on measurements of ASM or TSM—determined by several methods—in a sample of a healthy young adults in the age range within which muscle reaches a plateau and then remains relatively constant (18–40 years).

Computed tomography (CT) and MRI are considered the gold standards and the most accurate imaging methods for assessing SM, muscle cross-sectional area, and muscle quality [49]. However, due to the high cost and operational complexity of these methods, other imaging techniques, such as DXA and peripheral quantitative CT, have been recommended as accurate tools for assessing lean tissue or SM in both clinical and research contexts [50]. More recently, BIA technique has been used to estimate SM in clinical, research, and epidemiologic settings [51–52]. Estimates can be obtained by using BIA-derived TSM or ASM; their accuracy could depends on the methodology used to generate the body composition estimates [51–52] and the precision and validity of the equations. In the case of DXA-derived appendicular lean tissue, it is assumed that the entity measured represents limb SM mass or ASM with the additional assumption that limb SM mass represents 75% of the TSM. But DXA can also be used to estimate TSM by applying a correction factor of 1.33 [44].

Several cutoff points derived from samples of young adult populations have been obtained using the ASM, LBM, and TSM measured by DXA or BIA techniques (Tables 1.1 and 1.2). Recently, other cutoff points based on ASM or TSM measurements using old, new, and standard reference methodologies—including anthropometry in younger and older people [21,53], ultrasound in adults, and CT [54] and MRI [19] in subjects over a broad age range (18–78 years)—have been reported. Using specific cutoff points for different population sectors will enable researchers to more accurately assess the prevalence of sarcopenia across countries [49]. It has also been argued that applying gender- and ethnic-specific body composition predictive bioelectrical impedance or anthropometric equations, or gender- and ethnic-specific cutoff points, improves the accuracy of body composition estimates and diagnoses of sarcopenia [49]. On the topic of generating SM indices, Alemán-Mateo and Ruiz Valenzuela [32] recently published significant differences between the cutoff points based on DXA-derived SM indices in a young adult Mexican population with the cutoff points for a population of young male and female adult Caucasians from the United States and other ethnic groups. It was suggested that the indiscriminate use of published indices could produce biased results regarding the prevalence of low SM mass (presarcopenia) and sarcopenia syndrome in older people. Similar differences had been reported previously; for example, cutoff points for ASM for American females differed significantly from those for Italian women [55].

Table 1.1

DXA, dual-energy X-ray absorptiometry; ASM, appendicular skeletal muscle mass; TSM, total skeletal muscle mass (1.33*ASM); LMB, lean body mass; ht², height square; w%, weight, kg x 100; Class I, <1 SD; Class II, <2 SD of skeletal muscle indices (ASM, TSM, LBM).

Table 1.2

BIA, bioelectrical impedance analysis; ASM, appendicular skeletal muscle mass; TSM, total skeletal muscle mass (1.33*ASM); ht², height square; Class I, <1 SD; Class II, <2 SD of total skeletal muscle; w%, weight, kg x 100.

As mentioned previously, there are some BIA-derived SM indices. The usefulness and validity of the BIA technique for estimating SM is based on the relation between the volume of a conductor and its electrical resistance; there is a strong correlation between BIA resistance and SM measurements in the arms [56–57] and legs [57–58], and validity depends upon the criterion method for measuring SM. There are seven BIA-derived SM indices (ASMI and TSMI) generated in young adult populations from around the world, but it is important to note that most were derived from TSM measurements of young adult populations. The absolute values for BIA-derived TSM have also been adjusted by both height and body weight, while BIA-derived ASM have been adjusted only by height (Table 1.2).

Clinical Implications of the Indiscriminate Use of Different Published Indices

Currently, despite advances in defining and establishing diagnostic criteria for sarcopenia by the EWGSOP [46], IWGS [47], and AWGS [48], no universal consensus has been reached as to which criteria and method can best be used to measure SM, and which cutoff points should be applied to identify sarcopenia syndrome. This situation generates serious problems in determining the prevalence, effectiveness of clinical treatments, and prevention. With respect to the various published indices, their indiscriminate use in older adult populations from other countries or ethnic groups could result in over- or underestimations in the prevalence of sarcopenia in older people.

Recently, a systematic review of the literature by Pagotto and Silveira [59] concluded that the heterogeneity in the prevalence of sarcopenia was due to the diagnostic method and cutoff points chosen and the characteristics of both the study and the reference populations. On the specific question regarding cutoff points, these authors found that applying the ASMI classification criteria to other populations (n=18) resulted in sarcopenia prevalence ranged from 0.0% to 56.7% in men and from 0.0% to 33.9% in women. They sustain that these results can be attributed to racial characteristics and emphasize the effects of physical characteristics and cultural aspects that entail different levels of physical activity, distinct dietary regimes, and varying levels of quality of life among older adult populations in different countries. For example, the low prevalence encountered among a Chinese study group led the authors to conclude that ASMI is not an appropriate method for diagnosing sarcopenia in this specific population. The cutoff points for the Chinese population are lower than for Americans (<5.72 versus 7.26 kg/m² in men; <4.82 versus <5.45 kg/m² in women), with mean values derived from a young people of the same ethnic group were used as references. The mean ASMI of young Asians was approximately 15% lower than that of Caucasians, even after adjusting for height. Therefore, low muscle mass in young Asians will result in lower prevalence of sarcopenia in the elderly [59].

Around the time of the Pagotto and Silveira [59] publication, and as mentioned before we reported significant differences between the cutoff points determined by DXA-derived ASMI and TSMI from young adult subjects from different parts of the world and those derived from a group of young Mexican adult men and women [32]. More recently, Masanes et al. [60] assessed how changes in cutoff points for muscle mass, gait speed, and grip strength affected the prevalence of sarcopenia according to EWGSOP, 2010 criteria [46]. They found an increase from 5.45 to 6.68 kg/m² in the SM index for female outpatients and nursing-home residents, together with an increase in the prevalence of sarcopenia from 4% to 23% and 9% to 47%, respectively; the corresponding increases for men were 7.25–8.87 kg/m², and the prevalence of sarcopenia from 1% to 22% and 6% to 41%, respectively. Those authors further determined that changes in gait speed and grip strength had only a limited impact on the prevalence of sarcopenia. Their conclusion was that the cutoff points used for SM affect reported prevalence rates for sarcopenia, and as a result, interstudy comparability. Finally, according to their work, the main factors that influence the magnitude of change are the distribution of the SM index in the population and the absolute value of the cutoff points used, since the same difference between two references (e.g., 7.5–7.75 or 7.75–8 kg/m²) may produce variations in the prevalence [60].

In addition to gender, ethnicity, height, and body weight, other factors may also significantly affect SM mass or its indices and, therefore, the reported prevalence of sarcopenia. Tyrovolas et al. [61] have shown that lower levels of education and wealth, higher percentages of body fat, current consumption of alcoholic beverages, and having one chronic condition were all significantly associated with lower estimated SM indices. Importantly, higher percentages of body fat were consistently associated with lower estimated SM indices in all countries included in their study. This multicontinent study confirms the need for specific cutoff points for the ASM or TSM indices in the reference values derived from younger adult populations in order to ensure accurate diagnoses of low SM (presarcopenia) and sarcopenia syndrome [61].

Finally, these distinct indices of SM mass have been associated with other nutritional-related diseases or clinical entities, including vertebral hip fractures in women and hip and ankle fractures in older male Chinese subjects [13], while in elderly Korean people they have been related to bone mineral density and osteoporosis [62]. In Italy, meanwhile, low appendicular lean mass has been significantly associated with low bone mineral density in women with hip fractures [63]. Other studies have reported a significant association of low ASMI and obesity with insulin resistance, metabolic syndrome, and risk factors for cardiovascular disease [64]. There is also a recent report that weight-adjusted ASM was able to identify cardiometabolic risk factors such as triglycerides and high-density lipoprotein cholesterol, while height-adjusted ASM could identify factors for osteoporosis [65]. These findings highlight the relationship between SM indices and the risk of certain lifestyle-related diseases and clinical entities, though it is not yet clear what the best method or anthropometric variable for normalizing muscle mass might be. For this reason, cohort studies are required to clarify these associations by going beyond the classic association of SM indices with impaired physical performance and physical disabilities in geriatric populations.

Conclusions

There are several published cutoff points for TSMI and ASMI based on SM measurements by DXA and BIA for diagnoses of sarcopenia. It seems that the use of specific indices for different ethnic populations improves the accuracy of diagnoses of sarcopenia and decreases estimates of high prevalence generated by applying cutoff points derived from other populations. Based on the evident bias in diagnoses of the prevalence of sarcopenia produced by using nonethnic-specific reference values, the main challenge is to ensure that SM is measured by accurate and precise methods or estimated by valid BIA or anthropometric equations in young adult populations. These more accurate SM indices should be apply to estimate the prevalence of sarcopenia and other new clinical entities in geriatric populations. Finally, in the continuing absence of a universal consensus as to the best criteria and cutoff points available, using distinct cutoff points for specific ethnic groups is advisable for diagnosing sarcopenia, treating this condition, and preventing it in the growing older adult population worldwide.

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Chapter 2

Reduced Skeletal Muscle Mass and Lifestyle

David Scott¹, ²,    ¹Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia,    ²Department of Medicine—Western Health, Australian Institute for Musculoskeletal Science, The University of Melbourne, St Albans, VIC, Australia

Abstract

Skeletal muscle mass declines with age and the significant contribution of poor lifestyle behaviors may be the most modifiable causal factor. Observational studies in older adults demonstrate that maintaining greater physical activity, particularly at higher intensities, and intakes of dietary nutrients such as protein, omega-3 polyunsaturated fatty acids, and vitamin D may reduce age-related declines in muscle mass. Adequate dietary intake of key nutrients likely ensures exercise-induced muscle hypertrophy is maximized, and nutritional supplements may be beneficial for some older adults. Poor lifestyle behaviors such as smoking and excessive alcohol use may be detrimental for muscle mass, and given these are associated with poor socioeconomic status, interventions which reduce socioeconomic barriers to healthy lifestyle choices should be explored. Importantly, engaging in healthy behaviors from an early age will maximize peak muscle mass in young adulthood, and thereby minimize the risk of muscle insufficiency in older age.

Keywords

Muscle; aging; exercise; physical activity; nutrition; protein; vitamin D sarcopenia

From around the fifth decade of life, adults lose approximately 1–2 kg of skeletal muscle mass per decade [1]. Age-related declines in muscle mass occur due to reduced number and size of muscle fibers through processes of denervation, apoptosis, and atrophy [2]. In 1988, Irwin Rosenberg proposed the descriptor sarcopenia from the Greek sarx for flesh and penia for loss [3], but since then definitions of sarcopenia have evolved to also include poor muscle function [4,5]. Nevertheless, research has demonstrated that low muscle mass alone is associated with a range of health disorders including insulin resistance [6], cardiovascular disease [7], osteoporosis and fractures [8,9], as well as increased mortality [10]. Thus, strategies which can contribute to the maintenance of skeletal muscle during aging are likely to improve quality of life and longevity in the older adult population.

The plasticity of skeletal muscle to hypertrophic stimuli diminishes with age, but there are still opportunities to implement strategies to maintain muscle mass [11]. Lifestyle behaviors represent an attractive target because unlike other contributors to age-related muscle wasting, such as genetic and neuromuscular factors, they are inherently modifiable. Lifestyle modification strategies which can be implemented into public health recommendations can also potentially benefit a large proportion of the older adult population at relatively low costs compared with drug therapy interventions. This chapter summarizes current literature on associations of lifestyle behaviors and reductions in skeletal muscle mass during aging.

Physical Activity

Resistance training is the primary strategy recommended for older adults to maintain and improve both muscle mass and function [12]. A metaanalysis of 49 studies including over 1300 adults aged 50 years and older demonstrated that resistance training interventions result in mean improvements in lean body mass of around 1 kg, and this can be increased with higher volume [13]. Despite this, as few as 5% of adults over the age of 50 years meet guidelines for resistance training [14], suggesting that promotion is important in public health policies. However, aerobic exercise is also likely to be beneficial with master athletes (primarily runners, cyclists, and swimmers) who train 4–5 times per week demonstrating no significant declines in muscle with age [15].

Most observational studies explore associations between general physical activity (including both intentional and incidental movement) and muscle mass in older adults. Early studies utilized self-reported measurements of physical activity which are limited by recall bias but have demonstrated associations for self-reported physical activity, intensity of work activities, and performing exercise during leisure time, with higher muscle mass [16,17], and smaller declines in thigh girth over time [18]. Conversely, in a study of 337 US older adults, there was no association between self-reported physical activity and appendicular lean mass (the sum of lean mass in the arms and legs) [19], and odds for low appendicular lean mass normalized to height were not significantly decreased in participants of the New Mexico Elder Health Survey with high physical activity levels [20]. In Korean older men, likelihood for low appendicular lean mass normalized to body weight was 40%–70% lower in men with moderate and high levels of physical activity, but no such association was observed for women [21]. Furthermore, using the European Working Group on Sarcopenia in Older People (EWGSOP) definition of sarcopenia, which includes low gait speed and/or hand grip strength in addition to low relative appendicular lean mass [4], participants of the AGES-Reykjavik study who reported high levels of moderate-vigorous physical activity (MVPA) had around 40% lower 5-year incidence of sarcopenia, although MVPA was not significantly associated with rate of muscle loss [22]. The different instruments used to assess self-reported physical activity are likely to explain conflicting associations with muscle mass in these studies.

The advent of devices supporting objective assessments of physical activity has provided new opportunities to expand our understanding of its relationship with muscle mass in older adults. We previously reported that higher average steps per day counts, assessed by pedometers, are associated with higher leg lean mass over almost 3 years in older men and women of the Tasmanian Older Adult Cohort (TASOAC) study [23]. In the Nakanojo Study, a year-long assessment of physical activity using pedometers indicated positive effects of increasing steps/day on appendicular lean mass in older adults with a threshold at approximately 8000 and 6900 steps/day in men and women, respectively [24].

In TASOAC, accelerometers, which provide estimates of sedentary behavior and physical activity intensity by measuring accelerations (usually at the hip), demonstrated that sedentary time was associated with lower lean mass percentage. Furthermore, there was a dose–response relationship for physical activity, with MVPA associated with higher lean mass percentage than light physical activity, although the magnitude of association was lowest in the oldest age group [25], consistent with the decreasing plasticity of skeletal muscle with aging. Similar results were observed in a UK study of almost 1300 older men which reported that each additional 30 minutes/day of accelerometer-determined MVPA was associated with almost half the risk of severe sarcopenia (defined as low mid-upper arm circumference, hand grip strength, and gait speed), but light physical activity and sedentary time were not significantly associated with sarcopenia [26]. In the Nakanojo Study, older adults who spent <15 minutes/day at or above three accelerometer-determined metabolic equivalents, a level equivalent to moderate intensity physical activity, were more than twice as likely to have low appendicular lean mass relative to height compared with those who spent >23 minutes/day at this intensity [24]. Using ultrasound, Abe et al. also demonstrated that accelerometer-determined MVPA, but not light physical activity, was positively correlated with lower leg muscle thickness in older women [27].

Thus, objective assessments of physical activity generally demonstrate that MVPA is associated with greater muscle mass in older adults. While resistance training is likely to confer the greatest muscle mass improvements, minimizing sedentary behavior and increasing movement, particularly at higher intensities, should be a focus of guidelines for maintaining muscle mass during aging.

Nutrition

Dietary energy intake declines by up to 5000 kJ between the ages of 20 and 80 years [28]. This withdrawal of energy intake can contribute to weight loss which includes declines in skeletal muscle mass, and additional muscle mass and function deficits may occur due to inadequate intakes of specific macronutrients, micronutrients, and vitamins. Recent research has also focused on dietary patterns, which reflect how foods are consumed together, rather than as individual dietary components. Higher dietary variety is associated with greater mean arm muscle area and circumference in frail nursing home residents [29], and Chinese older adults with high scores on a diet quality index focusing on variety, adequacy, moderation, and overall balance of nutrition had half the likelihood of sarcopenia at baseline although not 4 years later [30]. In older Germans, adherence to a Mediterranean diet pattern was associated with greater appendicular lean mass relative to BMI and fat mass in women, but not men [31], and in the Helsinki Birth Cohort Study, adherence to the healthy Nordic diet was associated with better muscle strength, but not muscle mass [32]. To date, optimal dietary patterns for maintaining muscle mass during aging have not been thoroughly investigated, but future guidelines are likely to be informed by studies of specific nutrients.

Adequate dietary protein intake is a key nutritional component for skeletal muscle because protein contains amino acids, including essential amino acids which cannot be synthesized in the body, required for muscle protein synthesis [33]. Due to blunted muscle protein synthesis during aging, older adults may need to exceed current recommendations of 0.8 g/kg/day of dietary protein [34] and leucine (a branched-chain essential amino acid) may be particularly important for muscle mass [35–37]. For example, in older adults randomized to receive a drink containing 2–3 g of β-hydroxy-β-methylbutyrate (HMB; a leucine metabolite), as well as L-arginine and L-lysine (also essential amino acids) for 1 year, compared with those who received a nonessential amino acid drink, bioelectrical impedance analysis and dual-energy X-ray absorptiometry estimates of lean mass increased by 0.5–1 kg. Significant increases in whole-body protein turnover were also observed for the HMB/L-arginine/L-lysine group compared with controls at 12 months [38]. Nevertheless, in healthy older adults, there is limited evidence to suggest that protein or amino acid supplementation alone is beneficial for improving muscle mass [39].

Despite the mixed evidence for protein supplementation, longitudinal cohort studies support the beneficial role of higher dietary protein intakes in reducing muscle mass declines during aging. In the TASOAC study, older adults who reported failing to meet 0.8 g/kg/day of dietary protein had 0.8 kg lower appendicular lean mass than those who met or exceeded the recommendation, and baseline protein intakes were positively associated with change in lean mass over 3 years [40]. Older adults with dietary protein intakes in the lowest 20% in the US Health ABC Study also had around 40% greater decline in total and appendicular lean mass over 3 years [41], and in postmenopausal Australian women, baseline protein intake positively correlated with total and appendicular lean mass, up to 5 years later [42]. Protein sources may be an important consideration given meat contains higher amounts of essential amino acids; in the US Framingham Offspring Cohort, participants in the highest quartiles for total protein and animal protein had approximately 0.5 kg higher leg lean mass than those in the lowest quartiles, but leg lean mass did not differ across quartiles of plant protein intake [43] suggesting animal proteins are more beneficial for muscle mass in older adults. Distribution of protein consumption throughout the day may also influence muscle protein synthesis, with more even distributions across meals associated with higher lean mass in Canadian older adults [44].

Increased levels of inflammatory markers are associated with greater risk of sarcopenia [45]. Higher saturated and trans fatty acid intakes, associated with increased inflammation, were associated with lower fat-free mass, while the dietary ratio of polyunsaturated fatty acids (associated with decreased inflammation) to saturated fatty acids was positively associated with fat-free mass, in women in the TwinsUK study [46]. Omega-3 polyunsaturated fatty acids, primarily found in fish, plants, and nut oils, may enhance muscle mass by reducing inflammation and also by enhancing protein synthesis [2]. An 8-week trial in 16 older adults demonstrated that those randomized to receive omega-3 polyunsaturated fatty acids had increased muscle protein synthesis [47]. Similar effects have also been reported in a recent study of the effects of 16-weeks of omega-3 polyunsaturated fatty acids prior to and after a single bout of resistance exercise. Mixed muscle, mitochondrial, and sarcoplasmic protein synthesis rates increased prior to exercise, and mitochondrial and myofibrillar protein synthesis increased postexercise [48]. Six months of daily omega-3 supplementation (equivalent to the omega-3 polyunsaturated fatty acid content of 200–400 g of freshwater fatty fish) has also resulted in a 4% increase in muscle thigh volume compared to control in older men and women [49].

Age-related increases in accumulation of reactive oxygen/nitrogen species (ROS/RNS), known as oxidative stress, are thought to contribute to muscle mass decline through proteolysis which shifts protein balance into deficit [50]. Higher intakes of fruits and vegetables have been postulated to protect against muscle mass losses because they are a major dietary source of antioxidants [51,52]. In the Korean National Health and Nutrition Examination Survey, older men in the highest quintile for fruit and vegetable intake had approximately 70% reduced likelihood of low appendicular lean mass relative to height and fat mass, and a similar effect was seen for women with high fruit intake [53]. Achieving the recommended intake of vegetables in women (≥5 servings/day) was also associated with approximately half the likelihood for low muscle mass in the same cohort, although the effect of vegetable intake was not significant in men [54]. In Chinese older men, a high vegetables–fruits dietary pattern was also associated with 40% lower likelihood of sarcopenia [30]. In terms of specific antioxidants, selenium and vitamins A, C, and E intakes appear to be lower in older adults with low muscle mass and physical function [55–57].

Other nutrients associated with higher fruit and vegetable intakes may also contribute to maintenance of muscle mass during aging. Potassium plays a key role in muscle contraction, and dietary and urinary potassium have been positively associated with lean mass and muscle strength in older adults [58,59], although not changes in lean mass over 3 years [40,58]. Dietary magnesium may influence muscle adenosine triphosphate, and also inflammation [60]. Baseline magnesium intakes were 6% lower in sarcopenic compared with nonsarcopenic older adults in the PROVIDE study despite similar total energy intakes [56]. In TASOAC, energy-adjusted magnesium intake was a positive predictor of maintenance of appendicular lean mass over 3 years [40], and in the TwinsUK study, women in the highest quintile of magnesium intake had 0.4 kg/m² higher fat-free mass (normalized to height) than those in the lowest quintile; this effect size was seven times greater than that observed for higher protein intake [60].

Vitamin D, a secosteroid hormone produced in the epidermis following ultraviolet B light exposure and also obtained in smaller amounts from some foods, may have antiinflammatory properties [61]. Vitamin D deficiency is common in older adults due to lifestyle changes and age-dependent decreases in vitamin D metabolism [62]. In addition to indirect antiinflammatory effects, vitamin D may have direct effects on skeletal muscle as nuclear 1,25 vitamin D receptors (VDRs; which decrease with age) located in skeletal muscle may bind 1,25-dihydroxyvitamin D (1,25D; the active form of vitamin D) and promote protein synthesis [63]. Vitamin D may also augment mitochondrial oxidative phosphorylation in skeletal muscle [64].

Although VDR polymorphisms have been associated with low fat-free mass in older men [65], most research in this area focuses on 25-hydroxyvitamin D (25(OH)D) concentrations. 25(OH)D is produced in the liver and converted in the kidneys to 1,25D and levels less than 50 nmol/L are generally considered low and associated with increased falls and fracture risk through effects on muscle strength [66]. Effects on muscle mass are controversial however. Appendicular lean mass relative to body height was significantly lower in those with low 25(OH)D in the MINOS study of French middle-aged and older men [17], and in the Longitudinal Aging Study Amsterdam, odds for a loss of muscle mass greater than 3% over 3 years were around two times greater in older adults with low (<25 nmol/L) serum 25(OH)D levels, compared with participants with high (>50 nmol/L) 25(OH)D levels at baseline [67]. Conversely, in TASOAC, baseline 25(OH)D was a positive predictor of change in leg strength but not appendicular lean mass percentage over almost 3 years [68]. Dietary intakes of vitamin D have also been demonstrated to have no association with muscle mass in a cross-sectional older French women [69,70], although this may reflect the fact that relatively low proportions of total vitamin D are generally obtained from the diet. A recent analysis of the Concord Health and Aging in Men Project found that lower baseline levels of both 25(OH)D (<40 nmol/L) and the biologically active 1,25D (<62 pmol/L) are associated with over twofold increased odds of developing incident sarcopenia over the subsequent 5 years in men aged 70 years and older [71]. Given sarcopenia was defined in this study according to the Foundation for the National Institutes of Health definition (both low appendicular lean mass and low hand grip strength), it is not possible to determine whether the beneficial associations of 25(OH)D and 1,25D are attributable to effects on muscle mass and/or function.

Consistent with the concept that vitamin D may benefit muscle function but not muscle mass, a metaanalysis of vitamin D supplementation studies reported a small but significant positive effect on muscle strength relative to placebo or control, but no effect on muscle mass [72]. Vitamin D may therefore exert indirect effects on muscle function that are not explained by muscle mass [73], through improvements in neuromuscular factors such as coordination [74]. However, a small 4-month randomized controlled trial (RCT) in mobility-limited older women reported a significant increase in type II muscle fiber cross-sectional area in response to 4000 IU/day vitamin D3 compared with placebo [75], indicative of a benefit of vitamin D for muscle hypertrophy.

A combination of nutritional supplements may be most effective in ensuring adequate dietary intakes and improving muscle mass in older adults. In PROVIDE, a 13-week double-blind, placebo-controlled randomized trial of 380 sarcopenic older adults, participants randomized to a twice-daily nutritional supplement containing 20 g whey protein, 3 g total leucine, 9 g carbohydrates, 3 g fat, and 800 IU vitamin D demonstrated a significant gain in appendicular lean mass of almost 0.2 kg compared with controls, and also improved more in a sit-to-stand physical function test [76]. Further clinical trials are required to confirm the optimal combinations of nutrients and dosing regiments, and it is likely that not all older adults, particularly those with adequate diets, demonstrate muscle hypertrophy due to supplementation alone. Indeed, a recent systematic review concluded that three out of four nutritional supplementation RCTs indicated a positive effect on physical function, but not muscle mass in older adults [77]. Nevertheless, combination supplements may be effective at minimizing multiple nutritional deficiencies which contribute to muscle mass declines in older adults over the long term.

Combining Physical Activity and Nutrition

Given that adequate physical activity and nutrition are independently associated with improved muscle mass and function in older adults, combining these behaviors may be most beneficial. A recent metaanalysis concluded that, in healthy older adults, protein and amino acid supplementation may only improve muscle mass when combined with exercise [39]. Even moderate aerobic exercises may enhance muscle protein synthesis from protein supplementation [78], although in the US National Health and Nutrition Examination Survey (2003–06), significant positive associations for self-reported total beef and protein intakes with appendicular lean mass were observed only in middle-aged and older adults who reported participation in vigorous aerobic or muscle-strengthening exercise, rather than light intensity activity [79]. Adequate intakes of other nutrients in combination with physical activity may also be beneficial; women in the Korean National Health and Nutrition Examination Survey who achieved two, or three or more, healthy lifestyle behaviors (including adequate intake of meat, fish, eggs, and legumes; adequate intake of vegetables; adequate intake of fruits; sufficient moderate/vigorous intensity physical activity; and resistance exercise twice or more per week) had less than half the likelihood of low muscle mass compared with those who achieved no healthy behaviors [54]. Also, in over 600 community-dwelling older adults participating in TASOAC, participants who had high 25(OH)D and high physical activity levels at baseline lost significantly less appendicular lean mass (normalized to body weight) over 5 years, compared with those who had low vitamin D, low physical activity or low vitamin D, and low physical activity [80].

Factorial design RCTs are required to determine whether effects of exercise and nutrition interventions are synergistic (i.e., the combined benefits are greater than the sum of their individual benefits) [81], and few studies to date have been appropriately designed with adequate sample sizes. Based on the results of limited factorial RCTs, it is unclear whether benefits of combined protein supplementation and resistance training on muscle mass in older adults may be additive, rather than synergistic. In 155 Japanese women aged 75 years and older randomized to a 3-month exercise program and 3-g day of an amino acid supplement (containing 42.0% leucine, 14.0% lysine, 10.5% valine, 10.5% isoleucine, 10.5% threonine, 7.0% phenylalanine, and 5.5% other), exercise alone, amino acid supplement alone, or health education (control), a significant interaction was observed indicating greater leg muscle mass in the exercise plus supplement group compared with the health education group, although this improvement was not significantly greater than that observed for exercise or supplement alone groups [82]. Similarly, a 10-week factorial RCT in which obese older adults consuming a hypocaloric diet were randomized to a high vs low (1.3 g/kg/day vs 0.8 g/kg/day) with or without resistance training demonstrated no significant interaction effects, although fat-free mass increased significantly (0.6 kg) for the high protein plus training group only [83].

The majority of nonfactorial RCTs have investigated whether protein supplementation plus resistance training provides greater improvements in body composition and muscle function than resistance training alone. A recent metaanalysis of 49 trials in over 1800 adults not only reported significantly greater increases for fat-free mass and muscle cross-sectional area for resistance training when combined with protein intakes up to approximately 1.6 g/kg/day but also found that increasing age reduces these additive benefits [84]. Accordingly, some trials have not observed any effect of protein supplementation plus resistance training over resistance training alone for muscle mass in older adults [85,86]. Conversely, in female nursing home residents, 16 weeks of progressive resistance training combined with consumption 160 g of cooked lean red meat consumed 6 days per week resulted in 0.5 kg greater gains in total lean mass relative to progressive resistance training only [87]. In a 24-week study of frail older adults randomized to a twice-daily 250 mL protein drink (15 g protein) or placebo while completing resistance exercise, lean mass increased by 1.3 kg in the protein group but did not change in the placebo group [88].

Evidence is also lacking for a synergistic benefit of vitamin D (alone or in combination with protein) supplementation. A factorial RCT including 96 vitamin D deficient older adults randomized to 9 months of resistance training or no exercise, and to 400 IU/day per day of vitamin D plus calcium or calcium alone, observed no effects on muscle mass [89]. An 18-month factorial design RCT did demonstrate improved lean mass and muscle cross-sectional area in older men completing resistance training, but randomization to low-fat vitamin D fortified milk, providing an additional 1000 mg calcium, 800 IU vitamin D3, and 13.2 g protein per day, did not have additive or synergistic benefits [90]. However, in a two-arm RCT, early postmenopausal women who completed 24 weeks of resistance training while randomized to receive a supplement containing 10 g of whey protein, 31 g of carbohydrate, 1 g of fat, 200 IU of vitamin D, and 250 mg of calcium had an 0.8 kg increase in total lean mass, with no change observed for women in a placebo and resistance training group [91]. In a 12-week study, 130 sarcopenic older adults who participated in an exercise program including muscle-building, balance, and gait training, participants were randomized to receive an oral nutritional supplement containing whey protein (22 g), essential amino acids (10.9 g; 4 g leucine), and vitamin D (100 IU) or an isocaloric control. Participants in the supplement group gained an extra 1.7 kg of fat-free mass, and also had significant increases in appendicular lean mass relative to height, hand grip strength, and self-reported physical function, compared with placebo group [92].

The effects of antioxidant and omega-3 supplements on muscle mass have also been trialed in combination with exercise in older adults. A factorial RCT randomized 128 sarcopenic Japanese women to exercise plus tea catechin supplementation, exercise alone, tea catechin supplementation alone, or health education for 3 months [93]. Supplementation consisted of 350 mL of tea fortified with 540 mg of catechin (an antioxidant) each day for 12 weeks. Muscle mass changes did not differ between groups, but only the exercise plus tea catechin group demonstrated significant improvements in leg muscle mass from baseline to follow-up [93]. Fish oil supplements (rich in omega-3) have been shown to enhance improvements in muscle strength and function following a 12-week strength training program in older women [94], but it is unclear whether this relates to effects on muscle mass. Da Boit et al. randomized 50 older adults to receive 3 g of fish oil or safflower oil (placebo) each day during an 18-week lower-limb resistance exercise program but found no differences in the change in muscle cross-sectional area between groups [95]. This was consistent with a trial of 51 older adults who were randomized