Time to Reset: The Interplay Between Circadian Rhythms and Redox Homeostasis in Skeletal Muscle Ageing and Systemic Health.

Abstract

Skeletal muscle plays vital roles in locomotion, metabolic regulation and endocrine signalling. Critically, it undergoes structural and functional decline with age, leading to a progressive loss of muscle mass and strength (sarcopenia) and contributing to a systemic loss of tissue resilience to stressors of multiple tissue systems (frailty). Emerging evidence implicates misalignments in both the circadian molecular clock and redox homeostasis as major drivers of age-related skeletal muscle deterioration. The circadian molecular clock, through core clock components such as BMAL1 and CLOCK, orchestrates rhythmic gene, protein and myokine expression impacting diurnal regulation of skeletal muscle structure and metabolism, mitochondrial function, antioxidant defence, extracellular matrix organisation and systemic inter-tissue communication. In parallel, the master redox regulator, NRF2, maintains cellular antioxidant defence, tissue stress resistance and mitochondrial health. Disruption of either system impairs skeletal muscle contractility, metabolism, and regenerative capacity as well as systemic homeostasis. Notably, NRF2-mediated redox signalling is clock-regulated and, in turn, affects circadian clock regulation. Both systems are responsive to external cues such as exercise and hormones, yet studies do not consistently include circadian timing or biological sex as key methodological variables. Given that circadian regulation shifts with age and differs between sexes, aligning exercise interventions with one's own chronotype may enhance health benefits, reduce adverse side effects, and overcome anabolic resistance with ageing. This review highlights the essential interplay between circadian and redox systems in skeletal muscle homeostasis and systemic health and argues for incorporating personalised chrono-redox approaches and sex-specific considerations into future experimental research and clinical studies, aiming to improve functional outcomes in age-related sarcopenia and broader age-related metabolic and musculoskeletal conditions.