Metabolism and exercise: the skeletal muscle clock takes centre stage

• Published in: Nature reviews. Endocrinology Vol. 19; no. 5; pp. 272 - 284
• Main Authors: Martin, Ryan A., Viggars, Mark R., Esser, Karyn A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2023; Nature Publishing Group
• Subjects: 631/443/319/1557; 692/163/2743/2037; Animals; BMAL1 protein; Circadian Clocks - physiology; Circadian rhythm; Circadian Rhythm - physiology; Circadian rhythms; Endocrinology; Energy metabolism; Exercise; Gene expression; Gene Expression Regulation; Homeostasis; Humans; Mammals; Medicine; Medicine & Public Health; Metabolism; Muscle, Skeletal - metabolism; Musculoskeletal system; Physiology; Review Article; Skeletal muscle
• ISSN: 1759-5029; 1759-5037; 1759-5037
• DOI: 10.1038/s41574-023-00805-8

Circadian rhythms that influence mammalian homeostasis and overall health have received increasing interest over the past two decades. The molecular clock, which is present in almost every cell, drives circadian rhythms while being a cornerstone of physiological outcomes. The skeletal muscle clock has emerged as a primary contributor to metabolic health, as the coordinated expression of the core clock factors BMAL1 and CLOCK with the muscle-specific transcription factor MYOD1 facilitates the circadian and metabolic programme that supports skeletal muscle physiology. The phase of the skeletal muscle clock is sensitive to the time of exercise, which provides a rationale for exploring the interactions between the skeletal muscle clock, exercise and metabolic health. Here, we review the underlying mechanisms of the skeletal muscle clock that drive muscle physiology, with a particular focus on metabolic health. Additionally, we highlight the interaction between exercise and the skeletal muscle clock as a means of reinforcing metabolic health and discuss the possible implications of the time of exercise as a chronotherapeutic approach. The skeletal muscle clock directs a circadian programme of gene expression that is fundamental to both skeletal muscle and systemic energy metabolism. Notably, exercise timing can influence the skeletal muscle clock, which provides a rationale for exploring its potential role as a chronotherapeutic strategy. Key points The BMAL1–CLOCK heterodimeric transcription factor is a key regulator of clock output; partnership with MYOD1 confers muscle specificity. Skeletal muscle substrate preference, storage and transport are highly regulated by the skeletal muscle molecular clock, aligning metabolism with physical activity and feeding patterns. Mice with knockouts and mutations that affect the circadian clock, and behavioural misalignment in humans, as occurs in metabolic disorders such as type 2 diabetes mellitus, have severe metabolic consequences that affect insulin sensitivity and glucose handling. Exercise is a potent Zeitgeber that acts to shift skeletal muscle clocks; exercising at different times of the day results in divergent transcriptional and metabolic outputs. Differential time-of-day exercise might prove to be a useful chronotherapeutic strategy for the treatment and management of metabolic diseases by improving clock alignment and therefore metabolic regulation.