The MOTS-c K14Q polymorphism in the mtDNA is associated with muscle fiber composition and muscular performance

Hiroshi Kumagai, Toshiharu Natsume, Su Jeong Kim, Takuro Tobina, Eri Miyamoto-Mikami, Keisuke Shiose, Noriko Ichinoseki-Sekine, Ryo Kakigi, Takamasa Tsuzuki, Brendan Miller, Kelvin Yen, Haruka Murakami, Motohiko Miyachi, Hirofumi Zempo, Shohei Dobashi, Shuichi Machida, Hiroyuki Kobayashi, Hisashi Naito, Pinchas Cohen, Noriyuki Fuku*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Human skeletal muscle fiber is heterogenous due to its diversity of slow- and fast-twitch fibers. In human, slow-twitched fiber gene expression is correlated to MOTS-c, a mitochondria-derived peptide that has been characterized as an exercise mimetic. Within the MOTS-c open reading frame, there is an East Asian-specific m.1382A>C polymorphism (rs111033358) that changes the 14th amino acid of MOTS-c (i.e., K14Q), a variant of MOTS-c that has less biological activity. Here, we examined the influence of the m.1382A>C polymorphism causing MOTS-c K14Q on skeletal muscle fiber composition and physical performance. The myosin heavy chain (MHC) isoforms (MHC-I, MHC-IIa, and MHC-IIx) as an indicator of muscle fiber composition were assessed in 211 Japanese healthy individuals (102 men and 109 women). Muscular strength was measured in 86 physically active young Japanese men by using an isokinetic dynamometer. The allele frequency of the m.1382A>C polymorphism was assessed in 721 Japanese athletes and 873 ethnicity-matched controls. The m.1382A>C polymorphism genotype was analyzed by TaqMan SNP Genotyping Assay. Individuals with the C allele of the m.1382A>C exhibited a higher proportion of MHC-IIx, an index of fast-twitched fiber, than the A allele carriers. Men with the C allele of m.1382A>C exhibited significantly higher peak torques of leg flexion and extension. Furthermore, the C allele frequency was higher in the order of sprint/power athletes (6.5%), controls (5.1%), and endurance athletes (2.9%). Additionally, young male mice were injected with the MOTS-c neutralizing antibody once a week for four weeks to mimic the C allele of the m.1382A>C and assessed for protein expression levels of MHC-fast and MHC-slow. Mice injected with MOTS-c neutralizing antibody showed a higher expression of MHC-fast than the control mice. These results suggest that the C allele of the East Asian-specific m.1382A>C polymorphism leads to the MOTS-c K14Q contributes to the sprint/power performance through regulating skeletal muscle fiber composition.

Original languageEnglish
Article number130048
JournalBiochimica et Biophysica Acta - General Subjects
Volume1866
Issue number2
DOIs
Publication statusPublished - 2022 Feb

Keywords

  • Genetic polymorphism
  • MOTS-c
  • Muscle fiber composition
  • Muscular strength
  • Sprint/power performance

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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