Institute of Sports Medicine and Health, Chengdu Sport University, Chengdu 610041, China.
College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China.
Int J Mol Sci. 2024 Oct 7;25(19):10773. doi: 10.3390/ijms251910773.
Exercise is increasingly recognized as an effective strategy to counteract skeletal muscle aging and conditions such as sarcopenia. However, the specific exercise-induced genes responsible for these protective effects remain unclear. To address this, we conducted an eight-week aerobic exercise regimen on late-middle-aged mice and developed an integrated approach that combines mouse exercise-induced genes with human GWAS datasets to identify causal genes for sarcopenia. This approach led to significant improvements in the skeletal muscle phenotype of the mice and the identification of exercise-induced genes and miRNAs. By constructing a miRNA regulatory network enriched with transcription factors and GWAS signals related to muscle function and traits, we focused on 896 exercise-induced genes. Using human skeletal muscle -eQTLs as instrumental variables, 250 of these exercise-induced genes underwent two-sample Mendelian randomization analysis, identifying 40, 68, and 62 causal genes associated with sarcopenia and its clinical indicators-appendicular lean mass (ALM) and hand grip strength (HGS), respectively. Sensitivity analyses and cross-phenotype validation confirmed the robustness of our findings. Consistently across the three outcomes, , , , , and were identified as risk factors, while , , , , and were identified as protective factors, all with potential as biomarkers for sarcopenia progression. Biological activity and disease association analyses suggested that exercise exerts its anti-sarcopenia effects primarily through the regulation of fatty acid oxidation. Based on available drug-gene interaction data, 21 of the causal genes are druggable, offering potential therapeutic targets. Our findings highlight key genes and molecular pathways potentially responsible for the anti-sarcopenia benefits of exercise, offering insights into future therapeutic strategies that could mimic the safe and mild protective effects of exercise on age-related skeletal muscle degeneration.
运动正逐渐被认为是对抗骨骼肌衰老和肌少症等疾病的有效策略。然而，具体的运动诱导基因负责这些保护作用尚不清楚。为了解决这个问题，我们对中老年小鼠进行了八周的有氧运动，并采用了一种综合方法，将小鼠运动诱导基因与人类 GWAS 数据集相结合，以确定肌少症的因果基因。这种方法显著改善了小鼠的骨骼肌表型，并确定了运动诱导基因和 miRNA。通过构建一个富含与肌肉功能和特征相关的转录因子和 GWAS 信号的 miRNA 调控网络，我们关注了 896 个运动诱导基因。使用人类骨骼肌 -eQTLs 作为工具变量，对其中 250 个运动诱导基因进行了两样本 Mendelian 随机化分析，确定了 40、68 和 62 个与肌少症及其临床指标——四肢瘦体重 (ALM) 和手握力 (HGS) 相关的因果基因。敏感性分析和跨表型验证证实了我们发现的稳健性。在三个结果中一致地发现 、 、 、 、 和 是风险因素，而 、 、 、 、 和 是保护因素，所有这些都有可能作为肌少症进展的生物标志物。生物活性和疾病关联分析表明，运动主要通过调节脂肪酸氧化发挥其抗肌少症作用。基于现有的药物-基因相互作用数据，21 个因果基因是可用药的，为提供了潜在的治疗靶点。我们的研究结果突出了关键基因和分子途径，这些基因和分子途径可能对运动的抗肌少症益处负责，为未来的治疗策略提供了深入的见解，这些策略可以模拟运动对与年龄相关的骨骼肌退化的安全和温和的保护作用。
