Circadian Rhythms, Skeletal Muscle Molecular Clocks, and Exercise

Elizabeth A. Schroder; Karyn A. Esser

Disclosures

Exerc Sport Sci Rev. 2013;41(4):224-229. 

In This Article

Exercise and Circadian Rhythms

Wheel running or cage activity has long been used as a readout of circadian behavior, but the idea that physical activity/exercise and, more importantly, the timing of exercise could serve as an entrainment cue is relatively new.[25,31] Studies in the late 1980s and early 1990s were the first to show that novel wheel access at different times of day was sufficient to shift the phase of circadian activity rhythms in mice and hamsters.[5] Further studies demonstrated that exercise is a sufficient environmental cue to effect clock gene expression in the SCN (central clock) located in the hypothalamus of the brain.[12] These studies established that activity, in the form of access to a novel running wheel, during light conditions decreased peak expression of the clock genes Per1 and Per2 in the SCN. Schroeder et al.[25] took this idea farther, examining both timing of exercise as well as multiple bouts of exercise. They explored effects on the central clock using a scheduled exercise paradigm in control and mutant mice in which the central molecular clock mechanism was weakened.[25] In attempts to better mimic the timing of exercise in the human population, mice were allowed free access to a wheel, no access to a wheel, or access limited to 6-h time frames at the beginning or end of the dark or active phase for a minimum of 16 d. Similar to previous studies examining single bouts of exercise, they observed changes in the properties of the molecular clock in the SCN after 16 d in the control mice, suggesting that the phase shifts observed in previous studies were not solely an acute-phase response. Moreover, Per2:LUC amplitude was damped in mice with wheel access scheduled early in the dark phase but unaffected with scheduled activity late in the dark phase or with free access to wheel running, suggesting that the timing of exercise may be critical for the maintenance of molecular rhythms in the SCN. Using the vasoactive intestinal polypeptide knockout mouse, shown to have an unstable clock mechanism, they found that scheduled exercise functioned to enhance the stability of both activity and heart rate rhythms.

The core molecular clock gene Clock also has been demonstrated to be critical for healthy skeletal muscle because Clock-mutant mice exhibit approximately 30% reduction in normalized maximal force at both the muscle and single-fiber level.[1] In addition, myofiber architecture is disrupted, and mitochondrial volume is diminished. Recent work from Pastore et al.[19] supports these results. They demonstrated that CLOCK protein is critical for mitochondrial maintenance in skeletal muscle. Taking this a step farther, they examined the ability of Clock-mutant mice to adapt to chronic exercise and found that, despite the pathology as a result of the mutant Clock gene, the ability of these mice to adapt to chronic exercise was not changed. Using endurance training, they were able to rescue the metabolic defects resulting from loss of functional CLOCK protein partially.

Most studies of exercise and shifting of circadian rhythms have relied on endurance exercise paradigms. Less is known about the potential for resistance exercise, but Zambon et al.[34] reported that one bout of 60 contractions was associated with changes in molecular clock gene expression in skeletal muscle of humans. Experiments in neonatal cardiomyocytes have shown that contractile activity may modulate the molecular clock through the actions of the CLOCK protein. Histological and biochemical analysis demonstrated that CLOCK localizes to the z-disk in neonatal cardiomyocytes and translocates to the nucleus to influence gene expression in response to contractile activity. CLOCK localization at the z-disk puts CLOCK in an appropriate location to sense mechanical function associated with contractile activity.[22] Although these studies are suggestive that resistance exercise also can modulate molecular clock function in muscle, there is still much to be determined.

With more than 600 different muscles in the human body, comprising approximately 40% of total body mass, understanding the effects of exercise on the molecular rhythms in individual skeletal muscles may provide critical insight into systemic mechanisms contributing to daily rhythms. At this stage, there is only one study that has examined more than one muscle in mice exposed to scheduled bouts of either voluntary or involuntary endurance exercise for 2 h d-1in the light phase 4 h after lights on. In this study, the authors found a significant shift in clock gene expression (Per2:LUC bioluminescence) in three different skeletal muscles and the lung from exercised mice, whereas the molecular clock in the SCN remained unshifted, demonstrating that scheduled exercise can alter the molecular clock in peripheral tissues. In addition, one of the muscles examined, the flexor digitorum brevis was phase advanced more than the other two muscles (soleus and extensor digitorum longus), suggesting the potential for differential regulation of the molecular clock in individual muscles.[31] Lumicycle data, in combination with data demonstrating rescue of phenotype resulting from exercise,[19,25,31] implicate exercise as a nonphotic time cue in peripheral tissues and suggest that the molecular clock in all muscle tissues may not respond in a similar manner to nonphotic cues. Because muscle is such a large contributor to systems physiology, these data have broad implications for human health and disease, suggesting the power of exercise and, more specifically, the interaction of exercise and muscle as a therapeutic strategy to help stabilize/realign molecular clocks throughout the body.

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