BMAL1/PGC1α4-FNDC5/irisin axis impacts distinct outcomes of time-of-day resistance exercise

•The outcomes of resistance training are dependent on time of exercise in humans.•FNDC5/irisin mediates skeletal muscle strength and time-of-day-dependent resistance training outcomes.•FNDC5 is transcriptionally regulated by BMAL1/PGC1α4.•Irisin increases muscle hypertrophy via αV class of integrins and FAK-AKT-CREB signaling. 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. [Display omitted]