Kazan Hasan H, Kasakolu Anıl, Koncagul Seyrani, Ergun Mehmet A, John George, Sultanov Rinat I, Zhelankin Andrey V, Semenova Ekaterina A, Yusupov Rinat A, Kulemin Nikolay A, Larin Andrey K, Generozov Edward V, Bulgay Celal, Ahmetov Ildus I
Department of Medical Biology, Gulhane Faculty of Medicine, University of Health Sciences, Ankara, Türkiye.
Graduate School of Natural and Applied Sciences, Ankara University, Ankara, Türkiye.
Exp Physiol. 2024 Jul 23. doi: 10.1113/EP091992.
Insertions and deletions (indels) are the second most common type of variation in the human genome. However, limited data on their associations with exercise-related phenotypes have been documented. The aim of the present study was to examine the association between 18,370 indel variants and power athlete status, followed by additional studies in 357,246 individuals. In the discovery phase, the D allele of the MDM4 gene rs35493922 I/D polymorphism was over-represented in power athletes compared with control subjects (P = 7.8 × 10) and endurance athletes (P = 0.0012). These findings were replicated in independent cohorts, showing a higher D allele frequency in power athletes compared with control subjects (P = 0.016) and endurance athletes (P = 0.031). Furthermore, the D allele was positively associated (P = 0.0013) with greater fat-free mass in the UK Biobank. MDM4 encodes a protein that inhibits the activity of p53, which induces muscle fibre atrophy. Accordingly, we found that MDM4 expression was significantly higher in the vastus lateralis of power athletes compared with endurance athletes (P = 0.0009) and was positively correlated with the percentage of fast-twitch muscle fibres (P = 0.0062) and the relative area occupied by fast-twitch muscle fibres (P = 0.0086). The association between MDM4 gene expression and an increased proportion of fast-twitch muscle fibres was confirmed in two additional cohorts. Finally, we found that the MDM4 DD genotype was associated with increased MDM4 gene expression in vastus lateralis and greater cross-sectional area of fast-twitch muscle fibres. In conclusion, MDM4 is suggested to be a potential regulator of muscle fibre specification and size, with its indel variant being associated with power athlete status. HIGHLIGHTS: What is the central question of this study? Which indel variants are functional and associated with sport- and exercise-related traits? What is the main finding and its importance? Out of 18,370 tested indels, the MDM4 gene rs35493922 I/D polymorphism was found to be the functional variant (affecting gene expression) and the most significant, with the deletion allele showing associations with power athlete status, fat-free mass and cross-sectional area of fast-twitch muscle fibres. Furthermore, the expression of MDM4 was positively correlated with the percentage of fast-twitch muscle fibres and the relative area occupied by fast-twitch muscle fibres.
插入和缺失（Indels）是人类基因组中第二常见的变异类型。然而，关于它们与运动相关表型关联的有限数据已有记录。本研究的目的是检测18370个Indel变异与力量型运动员状态之间的关联，并在357246名个体中进行进一步研究。在发现阶段，与对照组（P = 7.8×10）和耐力型运动员（P = 0.0012）相比，MDM4基因rs35493922 I/D多态性的D等位基因在力量型运动员中过度表达。这些发现已在独立队列中得到重复验证，表明与对照组（P = 0.016）和耐力型运动员（P = 0.031）相比，力量型运动员中D等位基因频率更高。此外，在英国生物银行中，D等位基因与更大的去脂体重呈正相关（P = 0.0013）。MDM4编码一种抑制p53活性的蛋白质，p53可诱导肌纤维萎缩。因此，我们发现与耐力型运动员相比，力量型运动员股外侧肌中MDM4表达显著更高（P = 0.0009），且与快肌纤维百分比（P = 0.0062）和快肌纤维所占相对面积（P = 0.0086）呈正相关。在另外两个队列中也证实了MDM4基因表达与快肌纤维比例增加之间的关联。最后，我们发现MDM4 DD基因型与股外侧肌中MDM4基因表达增加以及快肌纤维更大的横截面积相关。总之，MDM4被认为是肌纤维类型和大小的潜在调节因子，其Indel变异与力量型运动员状态相关。要点：本研究的核心问题是什么？哪些Indel变异具有功能并与运动和锻炼相关特征相关？主要发现及其重要性是什么？在18370个检测的Indels中，发现MDM4基因rs35493922 I/D多态性是功能变异（影响基因表达）且最为显著，缺失等位基因与力量型运动员状态、去脂体重和快肌纤维横截面积相关。此外，MDM4的表达与快肌纤维百分比和快肌纤维所占相对面积呈正相关。
