A Role for Exercise to Counter Skeletal Muscle Clock Disruption

Melissa L. Erickson; Karyn A. Esser; William E. Kraus; ThomasW. Buford; Leanne M. Redman


Exerc Sport Sci Rev. 2021;49(1):35-41. 

In This Article

Abstract and Introduction


Disruption of the skeletal muscle circadian clock leads to a preferential shift toward lipid oxidation while reducing carbohydrate oxidation. These effects are apparent at the whole-body level, including glucose intolerance, increased energy expenditure, and fasting hyperglycemia. We hypothesize that exercise counters these metabolic disturbances by modifying the skeletal muscle clock and reverting substrate metabolism back toward an optimal substrate balance.


Temporal regulation of physiology and metabolism is governed by the circadian system. The core of this system is the molecular clock mechanism, which exists in every mammalian cell.[1] Molecular clocks in both central and peripheral tissues work in a synchronized manner to temporally orchestrate the expression of thousands of genes in anticipation of upcoming physiological events. The collective output of these molecular clocks consists of approximate 24-h biological cycles, known as circadian rhythms.[2] In humans, aspects of metabolism follow circadian rhythmicity. For example, endogenous plasma glucose concentrations peak early in the morning before waking.[3] Whole-body insulin sensitivity is greatest in the morning and decreases in the late afternoon.[4] Substrate utilization also is rhythmic; carbohydrate oxidation is greater in the morning and decreases at night, whereas lipid oxidation displays a reciprocal pattern.[5] In addition, resting energy expenditure is greatest during the day and is lowest during the biological night.[5] Notably, these rhythms reflect a typical and mostly healthy circadian pattern, but circadian rhythms are susceptible to disruption, which negatively impacts health. For example, disrupted molecular clock mechanisms cause temporal disorganization in physiological and metabolic processes, resulting in the development of chronic conditions including cardiometabolic disease.[6]

Contributing to approximately 40% of body mass, skeletal muscle is one of the largest organ systems in the body and is responsible for force production, locomotion, and posture.[7] In addition, skeletal muscle contributes to systemic physiology and metabolic processes. For example, it is the primary regulator of macronutrient metabolism[8] and also participates in abundant crosstalk mechanisms with other tissues such as the liver, adipose, pancreas, and skeletal system.[9,10] The skeletal muscle circadian clock is upstream of many cellular processes and temporally orchestrates gene expression that is necessary for fundamental functions, such as myogenesis, transcription, and metabolism.[11,12] Disruption of the skeletal muscle circadian clock alters substrate metabolism, which subsequently leads to peripheral insulin resistance and glucose intolerance, increased energy expenditure, and fasting hyperglycemia[13–15] observed at the whole-body level. Thus, proper function of the skeletal muscle circadian clock may be necessary for long-term cardiometabolic health.

Early evidence suggests that disruption of circadian rhythms may be actionable — an important point for the development of interventions designed to improve human health. Interventions aimed to restore the function of the molecular clock network, or optimize circadian timing, may lead to the restoration of circadian rhythms, thus, ameliorating cardiometabolic disease. For example, independent of diet composition, alterations to meal timing improves indices of cardiometabolic health in adults including reduced postprandial glucose,[16] reduced appetite,[17] and improved insulin sensitivity, β cell function, blood pressure, and markers of oxidative stress.[18] Exercise may be another behavioral strategy with strong potential to optimize the circadian network and promote health and longevity.[19] Although exercise has long been recognized for its disease-mitigating effects, all of the mechanisms by which exercise improves health are yet to be fully elucidated. It is possible that some exercise-induced health benefits are mediated through actions on the circadian clock in skeletal muscle. The skeletal muscle circadian clock is targetable with exercise[20,21] and, thus, is a viable candidate for restoring circadian function and improving health. Additional muscular properties improve with increased skeletal muscle contractility, including strength, function, and metabolic capacity. Thus, we hypothesize that exercise protects against cardiometabolic disease in part through actions on the skeletal muscle circadian clock. The objective of this narrative review is to highlight existing knowledge and gaps related to the connection between skeletal muscle circadian clock disruption to the development of cardiometabolic disease, as well as considerations of exercise as a therapeutic strategy for health restoration.