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The Journal of Clinical Endocrinology and Metabolism, 60, 513–516. 223 G.S. Lynch (ed.), Sarcopenia – Age-Related Muscle Wasting and Weakness, DOI 10.1007/978-90-481-9713-2_11, © Springer Science+Business Media B.V. 2011 Abstract Skeletal muscle is one of the most heritable quantitative traits studied to date, with heritability estimates ranging from 30% to 85% for muscle strength measures and 50–80% for lean mass measures. The strong genetic contribution to skeletal muscle traits indicates the possibility of using genetic approaches to indi- vidualize treatment approaches for sarcopenia or even aid in prevention strategies through the use of genetic screening prior to functional limitations. While these possibilities provide the rationale and motivation for genetic studies of skeletal muscle traits, few genes have been identified to date that appear to contribute to variation in either skeletal muscle strength or mass phenotypes, let alone sarcope- nia itself. The ACE, ACTN3, CNTF, and VDR genes have been associated with skeletal muscle strength in two or more papers each, while the AR, TRHR, and VDR genes have been similarly associated with muscle mass. Only the VDR gene has been significantly associated with sarcopenia itself as an endpoint phenotype but replication of this initial finding has not yet been performed. Large-scale clini- cal studies relying on advanced genome-wide association techniques are needed to provide further insights into potentially clinically relevant genes that contrib- ute to skeletal muscle traits, with identified genes then explored functionally to determine the likelihood that genetic screening can assist in the prevention and treatment of sarcopenia. Keywords Genotype • Heritability • Muscle mass • Muscle strength • Polymorphism Genetic Variation and Skeletal Muscle Traits: Implications for Sarcopenia Stephen M. Roth S.M. Roth (*) Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD 20742, USA e-mail: sroth1@umd.edu 224 S.M. Roth 1 Introduction Aging is associated with a decline in skeletal muscle mass, strength, power and physical functioning, generally termed sarcopenia (Dutta and Hadley 1995). These well-documented losses of muscle strength, mass, and muscle quality (limb strength/limb muscle mass) with age (Lindle et al. 1997; Baumgartner et al. 1998; Janssen et al. 2002; Lauretani et al. 2003; Sowers et al. 2005; Ploutz-Snyder et al. 2002) have important health consequences, because this deterioration in muscle structure and function is associated with an increased risk of falls, hip fractures, and functional decline (Schultz et al. 1997; Aniansson et al. 1984; Janssen et al. 2004; Newman et al. 2003a; Lauretani et al. 2003; Sowers et al. 2005). Muscle strength is independently associated with functional ability in the elderly (Hyatt et al. 1990; Visser et al. 2000a; Kwon et al. 2001; Purser et al. 2003; Rantanen et al. 1998; Foldvari et al. 2000; Lauretani et al. 2003; Pendergast et al. 1993) and may explain up to 25% of the variance in overall functional ability (Buchner and deLateur 1991). Furthermore, sarcopenia is related to a reduction in the performance of activities of daily living (Nybo et al. 2001), which may lead to further declines in muscle mass and strength and greater reductions in the performance of those activi- ties. The net effect of this cycle can result in marked disablement, predisposing older individuals to falls, injuries and disability (Rantanen et al. 2000). Although the loss of muscle mass is associated with the decline in strength in older adults, the strength decline is much more rapid than the concomitant loss of muscle mass, suggesting a decline in muscle quality (Goodpaster et al. 2006). The loss of muscle strength is an independent predictor of mortality in the elderly, more so than loss of muscle mass (Metter et al. 2002; Rantanen et al. 2000, 2003; Fujita et al. 1995; Laukkanen et al. 1995; Newman et al. 2003b). Thus, the relationship of muscle mass and strength to mortality may rest in the higher functional capacity associated with having more muscle strength and mass, and an inverse association with functional limitations and disability. Sex differences have been shown, with women showing an earlier age of onset of sarcopenia (Lauretani et al. 2003; Janssen et al. 2002), and a greater prevalence of functional impairment at any age in com- parison to men (Lauretani et al. 2003; Rantanen and Avela 1997; Ostchega et al. 2000; Dunlap et al. 2002; Visser et al. 2000b), most likely owing to their lower muscle mass and strength levels compared to men throughout the adult age span (Frontera et al. 1991; Lindle et al. 1997; Rantanen and Avela 1997; Lauretani et al. 2003). The consequences of sarcopenia-related disability are significant both in terms of personal quality of life and to the overall economy, with healthcare costs related to sarcopenia in the United States estimated to be $18.5 billion dollars for adults 60 years and older for the year 2000 (Janssen et al. 2004). Though the losses of muscle mass and strength begin on average between 40 and 50 years of age, losses for any particular individual are quite variable. For example, investigators from our laboratories at the University of Maryland have reported substantial age-related declines in strength and muscle quality in men and women from the Baltimore Longitudinal Study of Aging (BLSA) (Lindle et al. 1997; 225Genetic Variation and Skeletal Muscle Traits: Implications for Sarcopenia Lynch et al. 1999). However, we’ve observed enormous inter-individual variability in muscle strength within each age group that could not be explained by previous muscular activity levels. For example, the highest strength values for 80–96 year old men and women were two to four times higher than the lowest strength values in 20–39 year old men and women (Table 1). Furthermore, at least 15% of the men and women >60 year had strength values that were above the average values for 20 year old subjects. Similar inter-individual variations existed for leg muscle mass (Lindle et al. 1997) and for muscle quality in both older men and women (Lynch et al. 1999). Sarcopenia has been reported in community-dwelling men and women below the age of 50 year (Melton et al. 2000; Tanko et al. 2002; Janssen et al. 2002; Lauretani et al. 2003), and recently, sarcopenia associated with compromised physical functioning was shown to occur in nearly one in ten women aged 34–58 year (mid-life) (Sowers et al. 2005), providing further support for the variable onset of muscle strength losses and an indication of susceptibility to sarcopenia in some individuals. Various research groups are currently exploring the possibility that a portion of this inter-individual variability and susceptibility to early muscle losses is due to genetic factors, which could someday be used to identify susceptible men and women and individualize their prevention and treatment interventions. This review discusses the genetic aspects of skeletal muscle traits with an emphasis on sarcopenia, including examination of heritability, linkage analysis, and specific genes associated with relevant traits. While skeletal muscle remains one of the most heritable health-related quantitative phenotypes studied to date, the iden- tification of specific contributing genes remains at the early stages and much work remains to determine the future clinical importance of genetic contributions to sar- copenia risk. This review will not address the potential role of mitochondrial DNA mutations in the development of sarcopenia (Hiona and Leeuwenburgh 2008), as these genetic variations represent age-related, sporadic modifications of DNA sequence rather than stable, genome-wide genetic variants present since birth in all somatic cells. 2 Heritability of Skeletal Muscle Traits Variation in skeletal muscle traits among individuals can be attributed to environ- mental factors, genetic factors, or the interaction of both. While the influence of environmental factors such as physical activity and diet have been broadly investi- gated, only recently have studies begun to address the specific genetic influences on skeletal muscle traits that may explain the inter-individual variability noted above. The earliest of these studies examined familial aggregation of body compo- sition traits in twins, especially exploiting the slight but important differences between monozygotic and dizygotic twin pairs. Monozygotic twins share not only 100% of genetic variation in their DNA sequence, but also share the intrauterine environment and very likely a similar environment through adolescence. Dizygotic . (2001). Basal muscle amino acid kinetics and protein synthesis in healthy young and older men. JAMA, 286, 1206–1212. Welle, S. (2002). Cellular and molecular basis of age-related sarcopenia. Canadian. individuals. The Journal of Clinical Endocrinology and Metabolism, 60, 513–516. 223 G.S. Lynch (ed.), Sarcopenia – Age-Related Muscle Wasting and Weakness, DOI 10.1007/978-90-481-9713-2_11, ©. functioning, generally termed sarcopenia (Dutta and Hadley 1995). These well-documented losses of muscle strength, mass, and muscle quality (limb strength/limb muscle mass) with age (Lindle