Abstract
Accumulating evidence indicates that the circadian clock, a transcriptional/translational feedback circuit that generates ~24-hour oscillations in behavior and physiology, is a key temporal regulatory mechanism involved in many important aspects of muscle physiology. Given the clock as an evolutionarily-conserved time-keeping mechanism that synchronizes internal physiology to environmental cues, locomotor activities initiated by skeletal muscle enable entrainment to the light-dark cycles on earth, thus ensuring organismal survival and fitness. Despite the current understanding of the role of molecular clock in preventing age-related sarcopenia, investigations into the underlying molecular pathways that transmit clock signals to the maintenance of skeletal muscle growth and function are only emerging. In the current review, the importance of the muscle clock in maintaining muscle mass during development, repair and aging, together with its contribution to muscle metabolism, will be discussed. Based on our current understandings of how tissue-intrinsic muscle clock functions in the key aspects muscle physiology, interventions targeting the myogenic-modulatory activities of the clock circuit may offer new avenues for prevention and treatment of muscular diseases. Studies of mechanisms underlying circadian clock function and regulation in skeletal muscle warrant continued efforts.
Highlights
The circadian clock is the overt ~24-hour daily rhythm in physiology and behavior that evolved to respond to earth’s rotation
The central clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus and transmits timing signals from light inputs to drive peripheral tissue clocks[1,2,3]
The clock system in skeletal muscle has been recognized to play critical roles in key aspects of skeletal muscle physiology ranging from structural maintenance to functional regulation[6,7,8,9]
Summary
The circadian clock is the overt ~24-hour daily rhythm in physiology and behavior that evolved to respond to earth’s rotation. The skeletal muscle phenotypes found in genetic models of additional clock genes further support the notion that the molecular clock as a regulatory circuit exerts profound influence on skeletal muscle mass and function Both the clock repressor, Rev-erbα, and its reciprocal transcription activator RORα on the RORE responsive element have been implicated in the regulation of myogenic differentiation[42,43]. Locomotor activity may phase-coordinate the intrinsic rhythmic expression of genes in skeletal muscle with central clock-controlled sleep/wake cycles under normal physiological conditions These findings together indicate intimate interplays between muscle physical activity and the molecular clock machinery in skeletal muscle, the underlying mechanistic links, how activity-stimulated signals in muscle is transmitted to clock resetting, phase or amplitude modulation, remain to be elucidated. Future investigation into the molecular mechanisms linking clock and muscle metabolic substrate flux may yield novel targets for disease treatment including obesity and diabetes
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