Daily rhythms of light and darkness have been a part of human evolution. While some animals are more active nocturnally and humans tend to get exercise and food in the daylight hours, our evolutionary heritage may have led to shared similarities in how circadian genes orchestrate muscle cells’ response to the energy influx that comes with feeding (Kiriyama et al. 2022) and the physical stimulus that comes from exercise (Zambon et al. 2003). Maintenance of skeletal muscle requires ongoing remodeling, and when a misalignment occurs in the signals that circadian genes have evolved to rely on as cues for when to initiate their daily routines, the regular maintenance may not occur as scheduled, leading to the gradual decline in muscle mass seen in sarcopenia (Andrews et al. 2010). The possibility that the orchestration of these processes unfolds ideally in a context where circadian stimuli are strong and regular (Kume et al. 2020) points to future avenues of research to see whether intentional reinforcement of circadian rhythms through exercise timing and a consistent sleep schedule may be able to forestall the sarcopenia that is seen with aging.
This review discusses a survey of the current literature on the role of sleep schedule and circadian rhythms in the manifestation of sarcopenia, beginning with the association between sleep duration and sarcopenia. An association has been found with both short and long duration, but not with normal length sleep duration. Next, several human studies on circadian rhythm disruptions are discussed. Rodent studies investigating the involvement of circadian genes in the maintenance of skeletal muscle mass are noted. Finally, areas for future research as well as potential strategies to mitigate circadian disruptions through sleep and activity scheduling are explored.
PubMed, CINAHL, Medline, and Cochrane Register of Controlled Trials were queried using the search string (sarcopenia) AND (“circadian rhythm” OR sleep OR “shift work”). A total of 332 references were obtained from this initial search. Titles and abstracts were screened, as well as the references in relevant works, leading to the 23 studies included in this review. Rodent studies were included for their contribution to the understanding of gene expression dynamics.
The initial literature search returned 13 studies on the association between duration of sleep and sarcopenia. The majority of these found an association between both short (<6) and long (≥8 h) sleep duration and sarcopenia (Chien et al., 2015; Han et al., 2022; Hu et al., 2017; Huang et al, 2022; Li et al., 2023; Liu et al., 2023; Pourmotabbed et al., 2020; Rubio-Arias et al., 2019). Lucassen et al. (2017) and Szlejf et al. (2021) found no association between sleep duration and sarcopenia. Nakakubo et al. (2021), Shibuki et al. (2023), and Smith et al. (2022) found an association with long sleep duration, but not short sleep duration.
Choi et al. (2019) found that according to data from the 2008–2011 Korean National Health and Nutrition Examination Survey, those Koreans who had ever experienced the circadian disruption that results from the altered sleep schedule associated with shift work were more likely to exhibit sarcopenia than those who had worked exclusively during normal daytime hours (OR 1.7 +/- 0.2, CI 95%). If their work schedule had been irregular, the circadian disruption was seemingly greater, and the odds ratio for sarcopenia increased to 1.8 (1.3-2.4, CI 95%). 9,105 workers were included in this analysis, and sarcopenia, when defined as appendicular skeletal muscle mass to body mass index (BMI) ratio below the lowest quintile, was still associated with shift work when adjusted for shift work type, age, sex, BMI, fat mass, waist circumference, fasting blood glucose, metabolic syndrome, smoking, drinking, diet, exercise, sleep duration, education, income, and depression (p < 0.002).
Kume et al. (2020) investigated associations between sarcopenia and daily fluctuations in activity level, such as a well-defined period of the day when participants were at least moderately active, alternating with a solid resting time at night. Thirty participants wore wristwatches that tracked their activity levels 24 hours a day for one week as they went about their normal lifestyles. All participants were recruited from a sarcopenia rehab center and had exhibited signs of sarcopenia before participating in the study, but the study found that the 11 participants who met the Asian Working Group on Sarcopenia’s 2019 criteria for sarcopenia were not as active during the day, and there was more fragmentation in their active times, meaning their activity was broken up rather than being sustained as long before resting, compared to the participants who had not met the criteria for sarcopenia. Their rest-activity rhythms were also not as strong as the non-sarcopenic group when evaluated on the parameters of most active 10-h span (median 6,583 vs. 11,577 activity counts, ICR = 5,956 vs. 11,120, p < 0.02), least active 5-h span (median 1,628 vs. 755 activity counts, ICR = 866 vs. 858, p < 0.03), and the mean relative proportion between activity levels during these two spans on the average day (median 0.60 vs. 0.85, ICR = 0.46 vs. 0.14, p < 0.01; also correlated with measurement of time taken to walk four meters in the sarcopenic group, r = 0.77, p < 0.01). The authors note statistically significant differences in anthropometric measurements between the sarcopenic and non-sarcopenic participants (BMI 20.4 ± 3.5 vs. 24.5 ± 3.5 kg/m2, p < 0.004; Skeletal Muscle Mass Index 6.1 ± 0.8 vs. 7.4 ± 1.1 kg/m2, p < 0.002).
Yu et al. (2015) found that men who were more active in the evening (as determined by the Horne-Ostberg Morningness-Eveningness Questionnaire) were more likely to have sarcopenia (OR, 3.89; 95% CI, 1.33–11.33). These men reported their bedtimes as 11:53 ± 1:13, and waking times as 7:32 ± 1:23. Their sleep duration was not significantly different from those who were more active in the morning (6.7 ± 1.4 vs. 6.8 ± 1.1, p = 0.355), but the authors speculate that they could have been experiencing short sleep duration during the week and catching up on the weekends. Shift workers were not included in this study. Lucassen et al. (2017) also found an association between later sleep timing and sarcopenia.
In a randomized crossover study, Cedernaes et al. (2018) provide evidence for the existence of a molecular response to an acute disruption of circadian stimuli. They compared gene expression and levels of different proteins in muscle biopsies of healthy young men after a night of being kept awake with the lights on, compared to after a night when they had slept normally. They found that the night without sleep altered expression of the circadian gene Bmal1 in skeletal muscle (p < 0.017). Glycolysis did not proceed at the normal rate, and a catabolic environment was evident.
Kondratov et al. (2006) showed that mice missing the circadian gene Bmal1 develop sarcopenia at a younger age than normal mice; when they were as young as four months old in a breed that would live longer than two years without the mutation. They report that the muscle fibers of the mutant mice developed normally until they were about ten weeks old, but thereafter became increasingly both fewer and smaller in diameter than those of the normal mice. The lifespan of the mutant mice was half as long (37.0 ± 12.1 wk) and they were only able to attain half the size of a normal mouse before starting to lose muscle mass.
Andrews et al. (2010), in examining the gene expression of mutant mice, provide further evidence that circadian genes play a role in the muscle remodeling involved in the ongoing maintenance of muscle mass necessary to prevent sarcopenia. These mice had either a mutation (ClockΔ19) or an inactivation (Bmal1−/−) of a specific circadian gene. The authors had previously found that MyoD, whichplays a pivotal role in the formation of muscle fibers, had a circadian rhythm to its expression, and that MyoD loses its circadian rhythm when the circadian genes are disrupted. They suggest that the loss of this circadian rhythm would disrupt the optimal maintenance of muscle mass. Indeed, the muscle fibers of these mutant mice were seen to be abnormal in structure. Here they found that the CLOCK and BMAL1 proteins bind to the enhancer region of MyoD, thus elucidating the mechanism whereby MyoD and thus the muscle maintenance genes to which it binds in turn are expressed in circadian rhythm. Another finding was impaired mitochondria in the muscles of mutant mice, and the authors propose that this results from a failure of the Pgc-1 gene to be regulated in a circadian fashion by CLOCK and BMAL1.
Kiriyama et al. (2022) investigated the impact of altered feeding schedule as a form of circadian rhythm disruption to the muscles of mice. They found that circadian gene expression was altered in the muscle cells of the mice who skipped breakfast, setting the stage for a sarcopenic trajectory. The mice who skipped breakfast were not allowed access to food until four hours later than the control group of mice, who were allowed access at the beginning of the dark half of the day since mice are normally nocturnal. They observed that the mice who skipped breakfast exhibited disruption of the normal circadian rhythm in body temperature, which did not complete the normal daily rise until feeding commenced but then fell on schedule at dawn. Other observed alterations to biological circadian rhythms included insulin and corticosterone levels, which still peaked two hours after feeding commenced, but this was four hours later in the day for the mice who skipped breakfast. Several of the circadian genes that they monitored peaked their expression four hours later than normal as well. Peak triglyceride levels in the normal mice occurred at the midpoint of the dark/active 12-hour half of the 24-hour cycle, while for the mice who skipped breakfast, it did not occur until two hours after dawn. A decrease in skeletal muscle weight was observed in the mice who skipped breakfast. The authors conclude that skipping breakfast resulted in a misalignment of circadian gene expression, leading to loss of muscle mass. They propose that skipping breakfast may be a risk factor for sarcopenic obesity and recommend further studies into this area.
If disruption to circadian rhythm may be a risk factor for sarcopenia, it becomes desirable to find ways to reinforce circadian rhythms in order to support ongoing maintenance of skeletal muscle mass. Zambon et al. (2003) biopsied leg muscles of four untrained men (ages 31-51), after they had performed 30-45 minutes of vigorous exercise (knee extensions at 80% of 1-repetition maximum) with the right leg only. They found that, as they had anticipated, gene expression was different in the exercised compared to the non-exercised leg. After six hours, there were differences in the regulation of 704 genes, and by 18 hours post-exercise, between-leg differences were seen in 1,479 genes (p < 0.05). To look for differences associated with time rather than exercise, they compared gene expression between the two sampling times in the non-exercised leg and found differences in 608 genes. They identified three genes out of these 608 that were orthologous to mouse circadian genes and found that the upregulation of these three genes in the exercised compared to the non-exercised leg muscle at six hours post-exercise was statistically significant (expression increased by 1.5, 1.2, and 1.2 times, p < 0.05). The authors propose that the exercise regulated these genes directly, and that changes in expression of other genes may be a response to this shift in circadian rhythm. They suggest that future rodent studies will be a valuable addition to the body of knowledge on circadian genes and their role in skeletal muscle remodeling, and that by drawing on this knowledge, researchers can reduce the number of humans subjected to experimentation in pursuit of answers to the open questions around the role of circadian rhythm in conditions such as sarcopenia.
Eastman et al. (1995), in a human study to see whether exercise could help with adjustment to night shift, found that 8 participants who exercised for 15 minutes out of every hour during the first three nights of night shift, saw their body temperature graphs shift toward alignment with their new schedule by 6.6 ± 2.5 hours, compared to 4.2 ± 3.4 hours in the group who did not exercise (p = 0.06).
In line with the finding by Kume et al. (2020) that keeping activity up during the active portion of the day was associated with a lower rate of sarcopenia, Gianoudis et al. (2015), in a study of 162 adults over 60, found that regardless of overall physical activity levels, each hour of sedentary time such as television watching increased risk for sarcopenia by 33% (OR 1.33, 95% CI, 1.05, 1.68).
More studies need to be done with larger numbers of participants, to evaluate whether adjusting sleep and exercise can result in slowing or reversal of the progression of sarcopenia. Several of these studies acknowledged participant self-reporting of sleep or activity duration as a limitation to their results. There are limitations to the generalization from rodent studies to humans, and these results need to be interpreted in light of the differences known to exist between the two species. While the existing studies show an association between sarcopenia and disrupted circadian rhythm, causation is still theoretical in the absence of randomized controlled trials to observe a direct effect of an intervention.
Associations were found in human studies between sarcopenia and various aspects of sleep schedule and circadian rhythm disruption, including both long and short sleep duration; shift work; relative activity level between the most active and least active periods of the day; and evening activity level. On a molecular level, evidence was found in both human and rodent studies to support the suggestion that disruptions in circadian stimuli resulted in altered expression of circadian genes in muscle tissue. Providing insight into the potential for development of strategies to mitigate the circadian disruptions that are so commonplace in the modern lifestyle, 30-45 minutes of vigorous exercise was seen to increase expression of three circadian genes (Zambon et al., 2003).
Future studies could investigate the optimum time of day to schedule sleep, exercise and feeding, as well as exposure to both natural and artificial light, so that circadian rhythm disruptions will be mitigated, and the orchestration of muscle mass maintenance can be reinforced. Increasing exercise is one strategy for preventing sarcopenia (Aggio et al., 2016); perhaps its ability to help regulate circadian genes is one of the mechanisms underlying its benefit. Clinicians can monitor a patient’s sleep schedule and screen for common circadian rhythm disruptors and educate the patient on the importance of sleep hygiene, particularly if symptoms indicative of progression toward sarcopenia are already evident. While studies showing a direct benefit of an exercise or sleep schedule intervention to prevent sarcopenia are lacking, both of these practices have been shown to have multiple benefits that could be explained to the patient along with the theoretical potential in the realm of sarcopenia.
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