Myostatin Polymorphisms and Age‐Related Sarcopenia in the Italian Population

To the Editor: We read with great interest the paper recently published in the Journal by Seibert et al. 1 testing the hypothesis that the genetic variation of myostatin, a transforming growth factor-beta superfamily member, plays an important role in age-associated sarcopenia. The variability of the human myostatin gene was originally characterized by Ferrell et al., 2 who determined the nucleotide sequence for human myostatin in 40 individuals and found that two missense substitutions, specifically an A to G change at codon 55 in the exon 1 (A55T) and an A to G substitution in exon 2 (K153R), were appreciably represented in the U.S. population. Neither of these common polymorphisms had a significant effect on the magnitude of increment of muscle mass in response to strength training, although K153R was overrepresented in the nonresponders group. These findings are complemented by those obtained by Seibert et al., who found that the genotypes described by Ferrell et al. were very uncommon in the white population and noticed that older black women with an R153 allele tended to have low muscle strength. Using data from the InCHIANTI project, a large population-based epidemiological study of the causes and course of mobility disability in older persons, we estimated the prevalence of genetic variation of myostatin in the Italian population.3 Our purpose was to verify whether myostatin polymorphism may account for part of the variability in muscle mass and strength that is often found in older persons. From the original cohort of 1,306 participants who donated a blood specimen, we selected a random sample of 450 subjects (mean age ± standard deviation 69.5 ± 15.2, range 22–96; 189 men and 261 women). Using genomic deoxyribonucleic acid (DNA) extracted from whole blood, we applied the methods described by Ferrell et al. to search for the six polymorphisms identified in his original paper, with only one exception: the sequence of one of the primers used to amplify the nucleotide region of exon 1 containing the A55T was corrected by inserting a thymine 15 base pairs downstream of 5′. The A to G missense substitution at residue 55 in the exon 1 (A55T) was analyzed by polymerase chain reaction (PCR) amplification and AluI enzymatic digestion. Of the 450 DNA specimens, we found only two with an A55T polymorphism. Exon 2 was studied by PCR amplification followed by direct sequencing in 120 DNA samples. We observed only one of the five variants in the myostatin nucleotide sequence emphasized by Ferrell et al. Specifically, we found six heterozygous and 1 homozygous individuals for the K153R variant. An index of lower extremity muscle strength was obtained by calculating the harmonic average of the isometric strength assessed in eight muscle groups by a handheld dynamometer. The presence of a 153R allele was associated with lower muscle strength (153R+: 18.8 ± 2.2 kg; 153R−: 26.5 ± 1.0 kg; P = .05), although, after adjusting for age, such a difference was no longer statistically significant (P = .09). We also revealed in one subject a new missense single-nucleotide variation at codon 185, with a G to C substitution implicating the change of an argininic residue with a threonine. Our findings confirm those reported by Seibert et al. and suggest that the genotype K153R may be associated with accelerated sarcopenia.