Timing the effort: Chronobiological drivers of skeletal muscle adaptation and metabolic health.

Abstract

Exercise acts as a non-photic zeitgeber, resetting skeletal muscle circadian clocks that regulate metabolism, mitochondrial function, and insulin sensitivity. This review synthesizes current evidence on how exercise timing modulates skeletal muscle clock function and metabolic adaptation, with emphasis on divergent molecular pathways, sex-specific regulation, chrono-nutrition, and emerging evidence on immune-circadian interactions, myokine-mediated muscle-organ communication, and cellular stress responses. Exercise performed at different circadian phases activates distinct signaling networks despite identical mechanical workloads. Early active phase exercise, typically performed following an overnight fast, preferentially activates the AMPK-SIRT1-HIF1α axis, promoting lipid oxidation, metabolic stress sensing, and circadian phase advancement through PER/CRY modulation. Conversely, late phase exercise favors p38 MAPK-ATF2/CREB-PGC-1α signaling, enhancing mitochondrial biogenesis, oxidative phosphorylation, and Akt-AS160-GLUT4-mediated glucose disposal. Emerging evidence further suggests that circadian regulation of macrophage polarization, cGAS-STING signaling, contraction-induced myokine secretion, and proteostasis may contribute to time-dependent systemic adaptations, although direct human evidence remains limited. In addition, pronounced sexual dimorphism indicates that estrogen-mediated regulation of BMAL1/CLOCK signaling influences mitochondrial function and substrate selection. In conclusion, exercise timing represents an important regulator of metabolic health. Integrating circadian biology, nutritional timing, chronotype, sex, metabolic phenotype, and immune-metabolic context may facilitate the development of precision chrono-exercise strategies for metabolic and cardiometabolic disorders.