Molecular genetic studies of gene identification for sarcopenia

Abstract

Sarcopenia, which is characterized by a progressive decrease of skeletal muscle mass and function with aging, is closely related to several common diseases (such as cardiovascular and airway diseases) and functional impairment/disability. Strong genetic determination has been reported for muscle mass and muscle strength, two most commonly recognized and studied risk phenotypes for sarcopenia, with heritability ranging from 30 to 85% for muscle strength and 45-90% for muscle mass. Sarcopenia has been the subject of increasing genetic research over the past decade. This review is designed to comprehensively summarize the most important and representative molecular genetic studies designed to identify genetic factors associated with sarcopenia. We have methodically reviewed whole-genome linkage studies in humans, quantitative trait loci mapping in animal models, candidate gene association studies, newly reported genome-wide association studies, DNA microarrays and microRNA studies of sarcopenia or related skeletal muscle phenotypes. The major results of each study are tabulated for easy comparison and reference. The findings of representative studies are discussed with respect to their influence on our present understanding of the genetics of sarcopenia. This is a comprehensive review of molecular genetic studies of gene identification for sarcopenia, and an overarching theme for this review is that the currently accumulating results are tentative and occasionally inconsistent and should be interpreted with caution pending further investigation. Consequently, this overview should enhance recognition of the need to validate/replicate the genetic variants underlying sarcopenia in large human cohorts and animal. We believe that further progress in understanding the genetic etiology of sarcopenia will provide valuable insights into important fundamental biological mechanisms underlying muscle physiology that will ultimately lead to improved ability to recognize individuals at risk for developing sarcopenia and our ability to treat this debilitating condition.

Genetic aspects of skeletal muscle strength and mass with relevance to sarcopenia

“…Not all such genes are reviewed here, but the selected genes represent either those most studied or those with significant findings; a more comprehensive listing of genes was recently published. 25 The identification of genetic factors important to skeletal muscle strength is remarkably difficult given that multiple strength variables are commonly measured in different studies, including different muscle groups, contraction types and measurement instruments. Moreover, different genes are likely to contribute to different aspects of strength that may not be reflected across the different measurement types.…”

“…The importance of physical activity and resistance training particularly in slowing the losses of muscle mass and strength is clear 21,22 and genetic factors have been found important in this context, 23,24 but a discussion of that related literature is beyond the scope of the present review. Similarly, the present review focuses on human studies; readers are pointed to a more comprehensive review published recently 25 that discusses key findings from animal models that speak to the genetic aspects of skeletal muscle traits.…”

Association between polymorphisms in the TRHR gene, fat-free mass, and muscle strength in older women

“…Of note, these observations BMI body mass index, AFFM appendicular fat-free mass, TFFM total fat-free mass, PT peak torque remained significantly after adjustment for genomic African ancestry. A variety of previous reports had shown association between a reasonable number of candidate gene polymorphisms and muscle-related phenotypes, but with little agreement on significant contributors (Rankinen et al 2010;Lima et al 2011;Tan et al 2012). GWAS has become an important tool for better understanding the association between phenotypes and genotypes.…”

“…Thus, the present study provides evidence that the studied polymorphism (rs16892496) in the TRHR gene is one genetic variant AFFM appendicular fat-free mass, PT peak torque AGE (2013AGE ( ) 35:2477AGE ( -2483that contributes to FFM and muscle strength in crosssectional analyses, though its clinical relevance remains to be investigated. In fact, heritability of a variety of complex phenotypes is well documented in the literature (Thompson et al 2004;Tiainen et al 2009;Tan et al 2012); however, the contributory genes remain unclear. Understanding the relationship between genotypes and muscular phenotypes in the elderly might contribute to assist in an early intervention and allow preventive practices best suited to each individual, thus ultimately improving life quality in this population.…”

“…Identification of significant genetic variants underlying sarcopenia will provide valuable insights into important potential targets for risk stratification, as well as pharmacogenetic interventions aimed at increasing muscle mass and strength. Few genes have been identified to date, but lack of replication does not enable unequivocal conclusions (Tan et al 2012).…”