Loss of skeletal muscle with aging (sarcopenia) has emerged as a major public health issue. This loss of skeletal muscle mass is also frequently associated with other body composition changes (increased fatness) that have negative consequences for a variety of cardiovascular and metabolic risk factors. In this context, there is broad based interest in attempting to understand the biological mechanisms associated with these changes in body composition and in devising appropriate counter measures to limit them. Along these lines, three recent papers shed important new insight on issues that are likely to influence thinking about the mechanisms, consequences, and potential treatments of age-associated changes in muscle mass, body composition, and the related alterations in cardiovascular metabolic risk factors.
In the first paper, Walsh and colleagues (3) looked at how genetic variation in the androgen receptor (AR) might be associated with fat-free mass in older humans. These authors point out that androgen receptors are highly expressed in skeletal muscle, and that pathways governed by androgen receptors are subject to modification by physical activity. These pathways also play a key role in muscle mass, strength, and protein synthesis. The focus of their study is on the possibility that “CAG repeat polymorphisms” in the androgen receptor might contribute to the development and maintenance of skeletal muscle mass. The hypothesis was that individuals with a greater number of CAG repeats of the AR gene would have lower levels of fat-free mass compared with individuals with fewer CAG repeats. The basis of this hypothesis was previously reported, demonstrating that this polymorphism influences a variety of androgen-related conditions.
To test their hypotheses, the authors performed detailed body composition analysis on two well-characterized longitudinal cohorts of aging humans. In men, but not women, an increase in the number of CAG repeats was associated with greater fat-free mass in aging men. Additionally, there was an interaction between aging >22 CAG repeats and the decline in serum testosterone with aging. The authors discuss their results in the context of what is known about the androgen receptor and the influence of the CAG repeat number on various biochemical pathways. The authors also point out that the androgen receptor gene is now one of several on an increasing list of genes that might contribute to interindividual variation in skeletal muscle phenotype. They also note that their findings will have to be confirmed, and that their findings, if confirmed, raise a host of mechanistic issues related to the regulation of fat-free mass in humans.
In a second study, Schrager et al. (1) evaluated the influence of insulin-like growth factor II genotype on fat-free mass and skeletal muscle performance in humans. As is the case with the study on the androgen receptor CAG repeats, these authors point out that a variety of genetic factors might influence skeletal muscle phenotype (including IGF2). In this context, they evaluate the influence of a common polymorphism of the IGF gene on fat-free mass and muscle performance across the adult life span. The subjects under study were volunteers in the Baltimore Longitudinal Aging Study, and were subject to detailed measurements of body composition; muscle strength was tested using a variety of techniques. The authors conclude that their results partially support the primary hypothesis that individuals homozygous for the A allele IGF2 Apal locus possess lower fat-free mass, strength, and sustained power at age 35 and also at age 65. By contrast, individuals homozygous for the G allele fared better for each of these measures. A detailed discussion follows, discussing the potential role of IGF2 in modulating muscle mass during growth and development. This data is also framed in the context of recent ideas related to muscle-fiber number and muscle remodeling throughout life. The limitations of the study are discussed, and caution is expressed related to the difficulty in showing a clear relationship between variation at one gene locus and complex phenotypes such as muscle size and function. Issues related to sample size are also discussed. However, it is certainly reasonable to postulate an association between IGF2 genotype and muscle function in humans. Additionally, ideas about muscle growth and development, and how they influence the decline in muscle mass and muscle function with aging, are likely to be of increasing importance as evaluation of the mechanisms and consequences of sarcopenia continues.
The first two papers highlighted in this News Brief focused on emerging ideas about genetic variation and skeletal muscle mass and function throughout human life. Another age-related change in body composition that is equally problematic is the accumulation of visceral fat during aging. Although the factors contributing to this increase in visceral fat are complex, there also may be age-related hormonal changes associated with this problem. In this context, Villareal and Holloszy (2) reported the results of a randomized placebo-controlled trial of 6 months of dehydroepiandrosterone (DHEA) on abdominal and insulin action in elderly women and men. This trial is of interest for several reasons. First, DHEA is available without a prescription, and widely touted as an over-the-counter nutritional supplement that can reverse or limit many age-related conditions that might be associated with age-related changes in sex-steroid levels and metabolism. Second, there are animal studies suggesting that visceral fat accumulation with aging can be blunted or reversed with DHEA. Third, epidemiologic studies have been done in groups of individuals self-administering DHEA that show both positive and negative results.
The main results of this study are that in overweight males and females, DHEA supplementation caused significant reductions in visceral fat area and subcutaneous fat. Associated with these changes in body composition were glucose tolerance tests that suggested insulin sensitivity improved with DHEA in comparison to placebo. Based on these observations, the authors conclude that “DHEA replacement could play a role in prevention and treatment of the metabolic syndrome associated with abdominal obesity.” They also discuss how their findings relate to the animal studies and previous epidemiological findings. Finally, the authors point out that larger, more extensive trials will be needed.
The papers highlighted above are all related to aging, skeletal muscle function, and body composition changes. These issues are likely to be of great importance to exercise scientists because genetic factors that contribute to changes in skeletal muscle function and body composition are likely to interact with exercise training and chronic physical activity as determinants of both short- and long-term changes in skeletal muscle function and body composition. This information also is likely to be important in understanding how pharmacological approaches might be used to modify changes in body composition with aging. The provocative studies cited above represent some of the initial efforts to begin to understand how these factors interact to influence skeletal muscle function, body composition, and aging in humans.
1. Schrager, M.A., S.M. Roth, R.E. Ferrell, E.J. Metter, E. Russek-Cohen, N.A. Lynch, R.S. Lindle, and B.F. Hurley. Insulin-like growth factor-2 genotype, fat-free mass, and muscle performance across the adult life span. J. Appl. Physiol
. 97:2176–2183, 2004.
2. Villareal, D.T., and J.O. Holloszy. Effect of DHEA on abdominal fat and insulin action in elderly women and men: a randomized controlled trial. JAMA
3. Walsh, S., J.M. Zmuda, J.A. Cauley, P.R. Shea, E.J. Metter, B.F. Hurley, R.E. Ferrell, and S.M. Roth. Androgen receptor CAG repeat polymorphism is associated with fat-free mass in men. J. Appl. Physiol
. 98:132–137, 2005.