BackgroundPhysical activity is essential for maintaining muscle mitochondrial function and aerobic capacity. The molecular mechanisms underlying such protective effects are incompletely understood, in part because it is difficult to separate the effects of disease status and physical activity. We explored the association of human skeletal muscle transcriptomic with four measures of energetics and mitochondria oxidative capacity in healthy individuals.MethodsUsing RNA sequencing of vastus lateralis muscle biopsies from 82 GESTALT participants (52 males, aged 22–89 years), we explored gene and splicing variant expression profiles associated with self‐reported physical activity, peak oxygen consumption (VO2 peak), muscle oxidative capacity (kPCr) and mitochondrial respiration (Mit‐O2 flux). The effect of aging on gene expression was examined in participants with low and high VO2 peak.ResultsThe four measures of energetics were negative correlated with age and generally intercorrelated. We identified protein‐coding genes associated with four energetic measures adjusting for age, muscle fiber‐ratio, sex and batch effect. Mitochondrial pathways were overrepresented across all energetic variables, albeit with little overlap at the gene level. Alternative spliced transcript isoforms associated with energetics were primarily enriched for cytoplasmic ribonucleoprotein granules. The splicing pathway was up‐regulated with aging in low but not in high fitness participants, and transcript isoforms detected in the low fitness group pertain to processes such as cell cycle regulation, RNA/protein localization, nuclear transport and catabolism.ConclusionsA consistent mitochondrial signature emerged across all energetic measures. Alternative splicing was enhanced in older, low fitness participants supporting the energy‐splicing axis hypothesis. The identified splicing variants were enriched in pathways involving the accumulation of ribonucleoproteins in cytoplasmic granules, whose function remains unclear. Further research is needed to understand the function of these proteoforms in promoting adaptation to low energy availability.

中文翻译：

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骨骼肌 mRNA 剪接变异与 GESTALT 研究中四种不同的健康和能量测量的关联


背景体育锻炼对于维持肌肉线粒体功能和有氧能力至关重要。这种保护作用背后的分子机制尚不完全清楚，部分原因是很难区分疾病状况和身体活动的影响。我们探讨了人类骨骼肌转录组学与健康个体能量学和线粒体氧化能力的四种指标之间的关联。方法使用来自 82 名格式塔参与者 （52 名男性，年龄 22-89 岁） 的股外侧肌活检的 RNA 测序，我们探索了与自我报告的身体活动、峰值耗氧量 （VO2 峰值）、肌肉氧化能力 （kPCr） 和线粒体呼吸 （Mit-O2 通量） 相关的基因和剪接变异表达谱。在 VO2 峰值低和高的参与者中检查衰老对基因表达的影响。结果能量学的 4 个指标与年龄呈负相关，并且通常相互相关。我们确定了与调整年龄、肌纤维比例、性别和批次效应的四种能量测量相关的蛋白质编码基因。线粒体途径在所有能量变量中都过度代表，尽管在基因水平上几乎没有重叠。与能量学相关的选择性剪接转录物亚型主要富集于细胞质核糖核蛋白颗粒。在低适应度参与者中，剪接途径随着年龄的增长而上调，但在高适应度参与者中则不上调，在低适应度组中检测到的转录本亚型与细胞周期调控、RNA/蛋白质定位、核转运和分解代谢等过程有关。结论在所有能量测量中都出现了一致的线粒体特征。 支持能量剪接轴假说的年长、低健康参与者的选择性剪接得到增强。鉴定的剪接变体在涉及核糖核蛋白在细胞质颗粒中积累的途径中富集，其功能尚不清楚。需要进一步的研究来了解这些蛋白质形式在促进对低能量可用性的适应中的作用。