Resistance exercise leads to improved muscle function and metabolic homeostasis. Yet how circadian rhythm impacts exercise outcomes and its molecular transduction remains elusive. Human volunteers were subjected to 4 weeks of resistance training protocols at different times of day to assess training outcomes and their associations with myokine irisin. Based on rhythmicity of Fibronectin type III domain containing 5 (FNDC5/irisin), we trained wild type and FNDC5 knockout mice at late active phase (high FNDC5/irisin level) or late rest phase (low FNDC5/irisin level) to analyze exercise benefits on muscle function and metabolic homeostasis. Molecular analysis was performed to understand the regulatory mechanisms of FNDC5 rhythmicity and downstream signaling transduction in skeletal muscle. In this study, we showed that regular resistance exercises performed at different times of day resulted in distinct training outcomes in humans, including exercise benefits and altered plasma metabolomics. We found that muscle FNDC5/irisin levels exhibit rhythmicity. Consistent with human data, compared to late rest phase (low irisin level), mice trained chronically at late active phase (high irisin level) gained more muscle capacity along with improved metabolic fitness and metabolomics/lipidomics profiles under a high-fat diet, whereas these differences were lost in FNDC5 knockout mice. Mechanistically, Basic helix-loop-helix ARNT like 1 (BMAL1) and Peroxisome proliferative activated receptor, gamma, coactivator 1 alpha 4 (PGC1α4) induce FNDC5/irisin transcription and rhythmicity, and the signaling is transduced via αV integrin in muscle. Together, our results offered novel insights that exercise performed at distinct times of day determines training outcomes and metabolic benefits through the rhythmic regulation of the BMAL1/PGC1α4–FNDC5/irisin axis.

中文翻译：

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BMAL1/PGC1α4-FNDC5/irisin 轴影响每日不同时间阻力运动的不同结果


抗阻运动可以改善肌肉功能和代谢稳态。然而，昼夜节律如何影响运动结果及其分子转导仍然难以捉摸。人类志愿者在一天的不同时间接受为期 4 周的阻力训练方案，以评估训练结果及其与肌动蛋白鸢尾素的关系。基于含有 5 (FNDC5/irisin) 的纤连蛋白 III 型结构域的节律性，我们在活动后期（FNDC5/irisin 水平高）或休息后期（FNDC5/irisin 水平低）训练野生型和 FNDC5 敲除小鼠，以分析运动益处肌肉功能和代谢稳态。进行分子分析以了解骨骼肌中 FNDC5 节律性和下游信号转导的调节机制。在这项研究中，我们表明，在一天中的不同时间进行定期抗阻训练会给人类带来不同的训练结果，包括运动益处和血浆代谢组学的改变。我们发现肌肉 FNDC5/鸢尾素水平表现出节律性。与人类数据一致，与休息后期（低鸢尾素水平）相比，在活动后期（高鸢尾素水平）长期训练的小鼠在高脂肪饮食下获得了更多的肌肉能力，同时改善了代谢适应性和代谢组学/脂质组学特征，而这些差异在 FNDC5 敲除小鼠中消失了。从机制上讲，碱性螺旋-环-螺旋 ARNT 样 1 (BMAL1) 和过氧化物酶体增殖激活受体、γ、共激活因子 1 α 4 (PGC1α4) 诱导 FNDC5/irisin 转录和节律性，并且信号通过肌肉中的 αV 整合素转导。 总之，我们的结果提供了新颖的见解，即一天中不同时间进行的锻炼通过 BMAL1/PGC1α4–FNDC5/irisin 轴的节律调节来决定训练结果和代谢益处。