Myostatin and Follistatin Polymorphisms Interact with Muscle Phenotypes and Ethnicity

Abstract

Purpose We examined associations among myostatin (MSTN) 2379 A > G and 163 G > A and follistatin (FST) −5003 A > T and −833 G > T single nucleotide polymorphisms (SNP) on the muscle size and the strength response to resistance training (RT). Methods Subjects (n = 645, age = 24.1 ± 0.2 yr, body mass index [BMI] = 24.2 ± 0.2 kg·m−2) self-disclosed themselves as Caucasian (78.9%), African American (3.6%), Asian (8.4%), Hispanic (5.0%), or Other (4.2%). They were genotyped for MSTN 2379 A > G (n = 645), MSTN 163 G > A (n = 639), FST −5003 A > T (n = 580), and FST −833 G > T (n = 603). We assessed dynamic (one repetition maximum [1RM]) and isometric (maximum voluntary contraction [MVC]) muscle strength and size (cross-sectional area [CSA]) of the elbow flexors before and after 12 wk of unilateral upper-arm RT. Repeated-measures ANCOVA tested associations among genetic variants and muscle phenotypes with age and BMI as covariates. Results Baseline MVC was greater among African Americans who were carriers of the MSTN G2379 allele (AG/GG, n = 15) than the A2379A homozygotes (n = 8; 64.2 ± 6.8 vs 49.8 ± 8.7 kg). African Americans who were carriers of the FST T−5003 allele (n = 12) had greater baseline 1RM (11.9 ± 0.7 vs 8.8 ± 0.5 kg) and CSA (24.4 ± 1.3 vs 19.1 ± 1.2 cm2) than African Americans with the A-5003A genotype (n = 14; P < 0.05). No MSTN or FST genotype and muscle phenotype associations were found among the other ethnic groups (P ≥ 0.05). Conclusion MSTN 2379 A > G and FST −5003 A > T were associated with baseline muscle strength and size among African Americans only. These ethnic-specific associations are hypothesis generating and should be confirmed in a larger sample of African Americans.

Association of the K153R polymorphism in the myostatin gene and extreme longevity

“…The frequency of the R allele in the Spanish controls (~3 %) was similar to that previously reported in European Caucasians, i.e. 3-4 % with a frequency of mutant homozygotes (RR) below 1 % (Corsi et al 2002;Ferrell et al 1999;Kostek et al 2009). The frequency of the variant R allele and of R allele carriers was significantly higher in centenarians (7.1 and 12.8 %) than in controls (2.7 and 5.5 %) (χ 2 = 10.815, P = 0.001 and χ 2 = 8.546, P= 0.003, respectively).…”

The K153R variant in the myostatin gene and sarcopenia at the end of the human lifespan

“…Although more research is needed, the GDF8 K153R polymorphism has the potential to alter the function of the GDF8 gene (Ferrell et al 1999;Saunders et al 2006), as briefly explained below. Myostatin enters the bloodstream as a latent precursor protein and then undergoes a proteolytic process to become a mature peptide (free from the propeptide) that binds to extracellular activin type II receptor (ActRIIB) (Kostek et al 2009). Binding of myostatin to ActRIIB induces intracellular activation of Smad proteins; through this pathway, myostatin modulates myoblast proliferation (Thomas et al 2000) and differentiation (Ríos et al 2002), and thus ultimately muscle mass.…”

“…The Lys(K)153Arg(R) amino acid replacement is found within the active mature peptide of the myostatin protein and could theoretically influence (1) proteolytic processing with its propeptide or (2) affinity to bind with ActRIIB (Lee and McPherron 2001;Jiang et al 2004). This in turn would result in inability of myostatin to modulate muscle mass and strength (Kostek et al 2009). …”

“…Of the identified polymorphisms, the Lys(K)153Arg(R) variation located in exon 2 (rs1805086, 2379 A>G replacement) is a candidate to influence skeletal muscle phenotypes. The frequency of the mutant R allele is of about 3-4% among Caucasians, with a frequency of mutant homozygotes (RR) below 1% (Corsi et al 2002;Ferrell et al 1999;Kostek et al 2009). Such low allelic frequency certainly limits the possibility of studying large groups of people carrying the R variant.…”

“…Such low allelic frequency certainly limits the possibility of studying large groups of people carrying the R variant. Though controversy exists with regards to adults (Kostek et al 2009), the K153R polymorphism is associated with muscle strength, with the infrequent mutant R allele possibly exerting a negative influence in old (yet <80 years) Caucasian people (Ferrell et al 1999;Huygens et al 2004;Seibert et al 2001).…”