Clockwork conditioning: Aligning the skeletal muscle clock with time-of-day exercise for cardiometabolic health

Abstract

Circadian rhythms have evolved to synchronize gene expression, physiology, and behavior with time-of-day changes in the external environment. In every mammalian cell exists a core clock mechanism that consists of a transcriptional-translational feedback loop that drives rhythmic gene expression. Circadian disruption, as observed in shift workers and genetic mouse models, contributes to the onset and progression of cardiometabolic disorders. The central clock, located in the hypothalamus, is uniquely sensitive to external light cues, while the peripheral clocks are responsive to non-photic stimuli such as feeding and activity in addition to signals from the central clock. Recent research has illustrated the sensitivity of the skeletal muscle circadian clock to exercise timing, offering a promising avenue for therapeutic intervention in cardiometabolic health. Here we provide an in-depth examination of the molecular mechanisms underlying skeletal muscle clock function and its impact on cardiometabolic pathways, including glucose and lipid metabolism, as well as inflammation. To highlight the role of exercise as a time-cue for the skeletal muscle clock, we discuss evidence of exercise-induced shifts in the skeletal muscle clock and the differential response to exercise performed at different times of the day. Furthermore, we present data in support of time-of-day exercise as a potential therapeutic strategy for mitigating cardiometabolic disease burden. By exploring the relationship between the skeletal muscle clock, exercise timing, and cardiometabolic health, we identify new areas for future research and offer valuable insights into novel therapeutic approaches aimed at improving cardiometabolic disease outcomes.

Keywords: Cardiometabolic disease; Circadian rhythm; Exercise; Muscle clock; Skeletal muscle.

Fig. 1.

The core circadian clock mechanism. The core clock proteins BMAL1 and CLOCK heterodimerize and bind to E-box elements in the promoter region of various genes including the Per and Cry genes. Once translated, the PER and CRY proteins heterodimerize in the cytoplasm and form a protein complex with CKIε/δ, allowing them to translocate back into the nucleus and inhibit the activity of BMAL1 and CLOCK. Following expression promoted by BMAL1 and CLOCK binding, the ROR and REVERB proteins provide added regulation via promoting and inhibiting Bmal1 expression, respectively. Additionally, DBP and NFIL3 are involved in the transcriptional regulation of the RORs and REVERBs, providing another layer of regulation. This cell autonomous transcription-translation feedback loop cycles every ~24 h and set the foundation for circadian biology.

Fig. 2.

Time-of-day exercise alters the phase of the skeletal muscle clock. In-vitro, ex-vivo, and in-vivo models of skeletal muscle contraction and exercise produce phase shifts in core clock genes (such as PER2 shown here) towards the time at which the exercise was performed. The above graph represents the phase shift in PER2 rhythmicity observed with time-of-day exercise. The black line represents baseline rhythmicity while the red and blue dashed lines represent an exercise-induced phase delay and phase advance, respectively.

Fig. 3.

Consistent time-of-day exercise counteracts the negative effects of rotating shift work that lead to cardiometabolic disease. Chronic circadian misalignment, such as with rotating shift work, has been observed to lead to dysglycemia, dyslipidemia, chronic inflammation, and hypertension. Consistent time-of-day exercise can produce shifts in the skeletal muscle clock and promote rhythmic gene expression, thereby improving metabolic homeostasis. Exercise also has a potent anti-inflammatory effect and leads to decreased blood pressure overtime. Taken together, consistent time-of-day exercise works to inhibit the effects of chronic circadian misalignment.