Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan; The Leonard Davis School of Gerontology, University of Southern California, California, USA.
Faculty of Medicine, Tokai University, Kanagawa, Japan.
Biochim Biophys Acta Gen Subj. 2022 Feb;1866(2):130048. doi: 10.1016/j.bbagen.2021.130048. Epub 2021 Oct 30.
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.
人类骨骼肌纤维因其慢肌和快肌纤维的多样性而呈现异质性。在人类中，慢肌纤维基因表达与 MOTS-c 相关，MOTS-c 是一种已被鉴定为运动模拟物的线粒体衍生肽。在 MOTS-c 的开放阅读框内，存在一个东亚特异性的 m.1382A>C 多态性（rs111033358），该多态性改变了 MOTS-c 的第 14 位氨基酸（即 K14Q），从而降低了 MOTS-c 的生物学活性。在这里，我们研究了导致 MOTS-c K14Q 的 m.1382A>C 多态性对骨骼肌纤维组成和身体表现的影响。在 211 名日本健康个体（102 名男性和 109 名女性）中，使用肌球蛋白重链（MHC）同工型（MHC-I、MHC-IIa 和 MHC-IIx）作为肌肉纤维组成的指标进行评估。在 86 名身体活跃的日本年轻男性中，使用等速测力计测量肌肉力量。在 721 名日本运动员和 873 名种族匹配的对照组中评估了 m.1382A>C 多态性的等位基因频率。通过 TaqMan SNP 基因分型检测分析 m.1382A>C 多态性的基因型。与 A 等位基因携带者相比，m.1382A>C 多态性的 C 等位基因个体表现出更高比例的 MHC-IIx，这是快肌纤维的指标。携带 m.1382A>C 多态性 C 等位基因的男性腿部屈伸的峰值扭矩显著更高。此外，C 等位基因频率按短跑/力量运动员（6.5%）、对照组（5.1%）和耐力运动员（2.9%）的顺序升高。此外，年轻雄性小鼠每周接受一次 MOTS-c 中和抗体注射，持续四周，模拟 m.1382A>C 的 C 等位基因，并评估 MHC-快和 MHC-慢的蛋白表达水平。与对照小鼠相比，注射 MOTS-c 中和抗体的小鼠表现出更高的 MHC-快表达。这些结果表明，东亚特异性 m.1382A>C 多态性的 C 等位基因导致 MOTS-c K14Q 通过调节骨骼肌纤维组成，有助于短跑/力量表现。
