 yet been selected for study. An example of another potential inflammatory mediator of muscle growth is chemokine (C-C motif) ligand 2 (CCL2). CCL2 mRNA is dramatically upregulated following eccentric exercise [87, 88], and CCL2 is a key element in the interaction between macrophages and satellite cells [89]. Increased CCL2 expression could lead to enhanced recruitment of macrophages to the site of tissue injury, and greater expression of CCL2 by additional macrophages could enhance stimulation of satellite cells. Gene sequence variants in CCL2 that alter CCL2 levels [90] would be particularly interesting SNPs to evaluate with respect to muscle size and strength gain in response to resistance exercise, given that satellite cell activation by macrophages is a critical step in muscle repair and subsequent growth.
Inflammatory Cytokine Genomic Influences As mentioned above, inflammatory cytokines can have various roles in skeletal muscle, including regulating protein balance and satellite cell signaling. Given these roles, there are potential genetic variations in several cytokines and related genes could be associated with muscle strength and size traits in humans. The following section reviews the associations published to date on the TNF-alpha (TNF), IL6, CNTF and IL15 genes. It would be expected that individuals with genetic variants that elevate TNFalpha levels (promoting proteolysis) would have a hard time maintaining a positive protein balance. In fact, several SNPs in the promoter region (i.e., area of the DNA sequence with potential to alter transcription levels) of TNF have been tested. Liu et al. [91] reported lower muscle mass in men with variants in two SNPs (rs1799964 and rs1800630) that increase TNF-alpha mRNA expression, while SNP associations with strength varied with selected loci and sex/ethnicity subpopulations in that same study. The C (minor) allele of a SNP (rs1800795) in the IL6 promoter has been associated with higher plasma IL-6 levels in a cohort of ~1,000 myocardial infarction survivors [92]. Testing the hypothesis individuals with the variant associated with elevated IL-6 could have smaller muscles (theoretically from increased stimulation of proteolysis via TNF-alpha), Roth et al. [93] found lower fat free mass in men (but not women) with the CC genotype at the IL6 rs1800795 locus. Furthermore, Ruiz et al. [94] found the frequency of the GG genotype at the rs1800795 locus was significantly higher in elite power athletes (odds ratio of 2.4) than in elite endurance athletes or nonathlete controls. However, studies of IL6 genotypes with muscle strength have found limited association, with Walston et al. [95] finding no associations with IL6 promoter SNPs and muscle strength in older adults. In addition, Roth et al. [93] found no associations with strength across a large age span (20–92 years).
Based on the stimulatory effect of IL-15 on protein accretion in cell culture, p­ olymorphisms in IL15 and its receptor (IL15RA) have been hypothesized to be associated with muscle traits. However, only two IL15 association studies have been published to date. Pistilli et al. [96] found associations between the IL15RA rs2228059 genotype and baseline muscle size and quality (strength/size) in men but not women. This report also showed associations between the IL15 rs1057972 genotype and training induced strength gains in men, and between the IL15RA rs2296135 genotype and training induced strength gains in women. In an earlier study, Riechman et al. [97] found associations between IL15RA rs2296135 and lean body mass in men and women after resistance training, but no associations with strength. Several studies that examined muscle strength and size in association with variants in the CNTF gene and its receptor (CNTFR) have generated mixed results. Roth et al. [98] associated CNTFR genotype with both fat free mass and strength, while Arking et al. [99] and De Mars et al. [100] did not find size differences across various CNTF and CNTFR genotypes. Association studies between baseline strength with CNTF and CNTFR genotypes have yielded equivocal, often with sex specific, results. Only one study examined the effect of resistance training and CNTF genotype on muscle. Walsh et al. [101] reported strength, but not size, differences in women between rs1800169 CNTF genotypes, with G allele carriers stronger at baseline and gaining more strength with resistance training. These strength gains were seen in both arms following unilateral resistance training, suggesting a neuromuscular signaling mechanism rather than local muscular adaptations. This is a hypothesis supported by data from Conwit et al. [102] showing differences in motor unit activation between CNTF genotype groups. In summary, a number of associations between variations in genes coding for cytokines and muscle traits have been investigated. Results to date show variants in TNFA and IL6 (in men) are associated with lower muscle mass, although effects on muscle strength are not clear. Variants in CNTF and its receptor likely do not affect muscle size but may be related to neuromuscular signaling. Two studies suggest muscle size may be related to IL15 genotype, while strength results are again equivocal. It is possible that the higher sensitivity of size measures vs. the more variable nature of strength measures could account for these equivocal results. Differences in experimental groups and protocols used to investigate genetic associations of inflammatory genes with skeletal muscle traits also make it difficult to definitively conclude how much trait variability might be explained by inflammatory gene variations.
these three categories, a few gene associations with muscle traits have been found in genes outside of the normal hypertrophy pathways [103]. These include angiotensin 1 converting enzyme (ACE) and the vitamin D receptor (VDR). ACE typically affects blood flow, therefore ACE variations have most often been related to endurance muscle traits [103]. Associations between ACE genotype and strength have been investigated, yielding equivocal results [103–106]. VDR acts as a transcription factor and a nonhypertrophy related steroid receptor and is thought to relate to baseline muscle traits via effects on early muscle development [107]. As such, VDR polymorphisms have been related to baseline muscle strength [108, 109], but have not been studied in relation to changes following strength training. Even when associations are found between variants in these “orphan” genes and muscle traits, very small amounts of variability are explained. While it is biologically plausible, multiple SNPs in related genes (such as those within biological pathways such as AKT) may have additive effects (i.e., epistasis or multigene interactions); it is less plausible that variants in orphan genes such as ACE and VDR would contribute to additive effects, making their individual contributions to strength and size gains following resistance training marginal at best. At the current time, insufficient data exist to say these genes link to known strength and hypertrophy pathways.
and size), and environmental data like training status. Methods of systems biology modeling of gene networks are just being developed and applied to different ­diseases, and in the future could be applied to muscle traits like strength and size.
Practical Applications Skeletal muscle function is critical to athletes and nonathletes alike as a major contributor to quality of life, as well as athletic performance. Better understanding of the genetics underlying muscle strength and size could have several practical applications, including the advancement of personal genomics that can be used to predict who will respond positively and negatively to different interventions like exercise and drug therapy. For example, a genetic test for the ACTN3 R577X variant has been commercially available for years claiming to help people predict their “innate sports performance abilities,” including responsiveness to training. Thousands of these tests have been sold, often to parents who want to predict their children’s “athletic ability.” While current data do not support a high predictability of existing genetic tests for muscle traits such as ACTN3, improved test development with a better knowledge base could enable performance prediction capabilities. In addition to the use of exercise genomics to predict athletic performance, knowledge of muscle trait related loci could have more direct impact on current athletes if scientists determine how to exploit “good genes.” One example of this exploitation would be the development of a successful MSTN inhibitor, which does not currently exist on the market, but is in strong demand. How to prevent or regulate genetic manipulations or gene “doping” is an emerging field, tied to the advancement of knowledge of muscle related genes. While personalized training and gene doping are key applications of exercise genomics to current and future athletes, optimization of muscle health has applications to athletes and nonathletes alike. For example, individuals who have genetic backgrounds that are associated with lower strength may want to adopt strength training regimens, especially as they age to maintain healthy muscle function, which can influence other factors, such as body weight regulation and bone health. Another example would be the tailoring of rehabilitation programs after injury, based on genetic associations with strength development. Overall, musculoskeletal health across the population can be enhanced in the future with greater knowledge of genomic contributors to these health related traits.
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