Time to Train: The Involvement of the Molecular Clock in Exercise Adaptation of Skeletal Muscle

Abstract

Circadian rhythms regulate a host of physiological processes in a time-dependent manner to maintain homeostasis in response to various environmental stimuli like day and night cycles, food intake, and physical activity. Disruptions in circadian rhythms due to genetic mutations, shift work, exposure to artificial light sources, aberrant eating habits, and abnormal sleep cycles can have dire consequences for health. Importantly, exercise training efficiently ameliorates many of these adverse effects and the role of skeletal muscle in mediating the benefits of exercise is a topic of great interest. However, the molecular and physiological interactions between the clock, skeletal muscle function and exercise are poorly understood, and are most likely a combination of molecular clock components directly acting in muscle as well as in concordance with other peripheral metabolic organ systems like the liver. This review aims to consolidate existing experimental evidence on the involvement of molecular clock factors in exercise adaptation of skeletal muscle and to highlight the existing gaps in knowledge that need to be investigated to develop therapeutic avenues for diseases that are associated with these systems.

Physical activity as a promising alternative for young people with juvenile idiopathic arthritis: Towards an evidence-based prescription

“…For example, BMAL1 expression increase 1.6-fold 4 h after exercise, and 3.5-fold 8 h after an acute aerobic exercise bout of 70 min at 70% of the VO 2max in trained adults (85). On the other hand, exercise capacity can be modulated by the expression of BMAL1, CRY1 and PER2, via the regulation of mitochondrial function and the modulation of lipid and glucose metabolism (68). Of note, Basti et al (86) report that circadian oscillation of exercise performance seemed dependent in amplitude on BAML1 expression and in phase on expression of PER2 (86).…”

“…These proteins reach their peak activity during the inactive phase (i.e., at night) and bind to the enhancer (E)-box elements in the nucleus to drive the transcription of the Period (PER) and Cryptochrome (CRY) genes, which exhibit peak activity at the beginning of the active phase and inhibit CLOCK and BMAL1 activities. The opposite effects on the feedback loop are driven by the retinoic acid-related orphan receptors (ROR), which activate REV-ERBs (receptor subfamily 1 group D member 1) which inhibit BMAL1 transcription ( 68 ). Some of these clock proteins have central functions in inflammation and metabolism such as REV-ERBα regulates skeletal muscle oxidative capacity by modulating mitochondrial biogenesis and fatty acid oxidation ( 68 ).…”

The role of circadian rhythm in osteoporosis; a review

“…ROR and REV-ERB are important regulators of this feedback loop ( Liu et al, 2008 ; Gustafson & Partch, 2015 ; Mansingh & Handschin, 2022 ). The transcription and translation of REV-ERB is activated by the CLOCK-BMAL1 heterodimer and inhibited by CRY/PER, resulting in circadian rhythm changes in REV-ERBα ( Liu et al, 2008 ; Gustafson & Partch, 2015 ).…”

Homo sapiens May Incorporate Daily Acute Cycles of “Conditioning–Deconditioning” to Maintain Musculoskeletal Integrity: Need to Integrate with Biological Clocks and Circadian Rhythm Mediators

“…Of relevance to the topic at hand is the finding that exercise can entrain the biological clocks of tissues of the MSK system and, thus, there is integration of the central and tissue-specific peripheral circadian rhythms and exercise, or biomechanical loading is an important component of that potential integration. That leads to the question of “what is the best time to exercise in order to achieve the best integration and perhaps, the best outcomes?” [ 106 , 107 , 108 ]. As presented by Brito et al [ 106 ], evening exercise for humans, prior to the rest/inactivity part of the day, may offer better outcomes than morning exercise.…”