Stable clocks, rewired rhythms: circadian remodeling in skeletal muscle during aging, cachexia, and type 2 diabetes

In mammals, nearly every cell contains an intrinsic circadian clock that functions both as a timekeeping system and an environmental sensor, integrating external cues to maintain alignment between internal physiology and the external environment. While the core clock machinery is broadly conserved across tissues, its downstream rhythmic gene programs are highly tissue-specific and essential for maintaining cellular and physiological homeostasis. In the skeletal muscle, rhythmic program dysregulation has emerged as a common denominator in many unfavorable conditions. However, high-resolution circadian time-course studies in the muscle remain limited. In this review, we examine current evidence on the behavior of the skeletal muscle molecular clock and rhythmic transcriptional programs across aging, cancer-induced muscle atrophy (cachexia), and type 2 diabetes (T2D). Despite distinct pathological contexts, all three conditions undergo substantial condition-specific remodeling of the muscle rhythmic gene program, often converging on biological processes such as lipid metabolism and chromatin regulation. Collectively, available data suggest that circadian dysfunction in these conditions arises not from collapse of the core molecular oscillator but from progressive rewiring of rhythmic transcriptional programs despite relative preservation of core clock integrity. We discuss emerging mechanisms-including metabolic remodeling, glucocorticoid signaling, chromatin regulation, and noncanonical clock regulators-that may underlie this process. Moving forward, multi-omics studies integrating transcriptomic, proteomic, metabolomic, and epigenomic time-series analyses will be essential to distinguish mechanisms responsible for condition-specific rhythmic gene regulation. A clearer understanding of how rhythmic gene programs are rewired may reveal new opportunities to restore temporal coordination and improve skeletal muscle health across diverse pathological conditions.