Sutton Elizabeth, Pekovic-Vaughan Vanja
Institute of Life Course and Medical Sciences, Department of Musculoskeletal & Ageing Science, University of Liverpool, Liverpool L7 8TX, UK.
Antioxidants (Basel). 2025 Sep 18;14(9):1132. doi: 10.3390/antiox14091132.
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.
骨骼肌在运动、代谢调节和内分泌信号传导中发挥着至关重要的作用。至关重要的是，随着年龄的增长，它会经历结构和功能的衰退，导致肌肉质量和力量逐渐丧失（肌肉减少症），并导致多个组织系统对压力源的组织弹性系统性丧失（衰弱）。新出现的证据表明，昼夜分子时钟和氧化还原稳态的失调是与年龄相关的骨骼肌退化的主要驱动因素。昼夜分子时钟通过诸如BMAL1和CLOCK等核心时钟组件，协调有节奏的基因、蛋白质和肌动蛋白表达，影响骨骼肌结构和代谢、线粒体功能、抗氧化防御、细胞外基质组织和全身组织间通讯的昼夜调节。同时，主要的氧化还原调节因子NRF2维持细胞抗氧化防御、组织应激抗性和线粒体健康。任何一个系统的破坏都会损害骨骼肌的收缩性、代谢和再生能力以及全身稳态。值得注意的是，NRF2介导的氧化还原信号是由时钟调节的，反过来又影响昼夜节律时钟调节。这两个系统都对运动和激素等外部线索有反应，但研究并不总是将昼夜节律时间或生物性别作为关键的方法变量。鉴于昼夜节律调节随年龄变化且存在性别差异，使运动干预与自身的生物钟类型相匹配可能会增强健康益处、减少不良副作用，并克服与衰老相关的合成代谢抵抗。本综述强调了昼夜节律和氧化还原系统在骨骼肌稳态和全身健康中的重要相互作用，并主张将个性化的生物钟 - 氧化还原方法和性别特异性考虑纳入未来的实验研究和临床研究中，旨在改善与年龄相关的肌肉减少症以及更广泛的与年龄相关的代谢和肌肉骨骼疾病的功能结果。
