Using Body Clock Types to Help Keep Muscle Size, Quality, and Strength

Environmental factors affect the central circadian clock, which transmits the rhythms to the peripheral clocks and the clock-controlled genes. Light, or the daily light–dark cycle, is the primary environmental cue that sets the 24 h oscillations of circadian rhythms in the organism. Another major influencer on these 24 h oscillations is food intake, more specifically, the feeding-fasting cycles in addition to the composition of food intake (the macronutrients) [,]. Circadian oscillations are generated at a cellular level, a core mechanism found in most cells and known as the cell-autonomous transcriptional-translational feedback loop (TTFL) [,]. ^{11 24 25 26}

Circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like protein-1 (BMAL1) are considered core components of the mammalian circadian clock. BMAL1 heterodimerizes with CLOCK to form the BMAL1:CLOCK complex, which can then act as a transcriptional factor regulating genes involved in circadian rhythms by binding to specific cis-acting DNA sequences or E boxes. The BMAL1:CLOCK complex regulates a wide range of circadian outputs via the activation or repression of the transcription of genes encoding protein synthesis participating in circadian rhythms [,]. ^{27 28}

The transcription factors BMAL1 and CLOCK form heterodimers, which bind to the E-box located in the promoter regions of the period (per) and Cryptochrome (cry) genes to promote the production of PER and CRY proteins. When they accumulate to a certain level in the cytosol, PER and CRY translocate to the nucleus to inhibit the activity of the BMAL1:CLOCK complex, thus repressing their own expressions []. In addition, a secondary feedback loop involving the nuclear receptors ROR and REV-ERB modulates BMAL1 transcription by activating or repressing its expression through direct binding to ROR/REV-ERB response elements (RREs) within the BMAL1 promoter []. These core clock components regulate hundreds of other genes, called clock-controlled genes (CCGs) in a circadian manner (). Generally, core clockwork mechanisms exist in most tissues and cells of the body, but the expression of CCGs varies by cell type []. ^{29 30} Figure 1 ²¹

The circadian clock significantly influences body composition by regulating metabolism, eating patterns, and energy storage and expenditure. Disruption of circadian rhythms, such as erratic eating patterns or shift work, can lead to metabolic disorders, obesity, and changes in body composition. Conversely, optimizing eating patterns aligned with circadian rhythms while maintaining regular eating cycles can have a positive impact on body composition [43].

It has been established that the quantity and quality of food in meals are not enough as determinants of metabolic health. A study performed in 2014 [44] on adolescents has revealed that ETs had a small but significantly increased body mass index (BMI) in comparison to MTs. They also documented different dietary behaviors for ETs, highlighted by inadequate daily intake of fruits and vegetables, increased consumption of unhealthy snacks and increased consumption frequency of nighttime caffeine [44]. It has been shown that people who have a higher caloric intake during the final hours of the day, when the increase in melatonin secretion begins (which usually occurs 2–4 h before falling asleep), show an increase in fat storage, which is associated with a higher BMI [45]; thus, increasing the risks of obesity and cardiovascular diseases [39,46]. Another study performed in Japan [47] with female students aged 18–22 years as participants has observed a significantly lower skeletal muscle index (SMI) and significantly higher body fat percentage in ETs compared to non-ETs. No significant differences in total energy intake between MTs and ETs were recorded; however, the distribution of nutrients differed greatly, with ETs tending to have irregular eating patterns along with skipping meals and consuming most of their calories in the evening and/or at nighttime. A connected study has also reported different patterns in behavior related to physical activity; ETs have the tendency to be significantly less active than MTs when excluding academic and social obligations [48]. When chronotype and metabolic health were tested in Korean adults aged between 40 and 69 years, out of 1620 individuals enrolled in the study, 5.8% were considered as ETs and they showed increased prevalence of diabetes, metabolic syndrome and sarcopenia along with an increased fat mass in women and decreased lean mass in men [31]. The misalignment between internal and external rhythms is greatest in ETs [31]. On weekdays, ETs tend to have sleep debts due to insomnia and other sleeping disorders, which leads to extended sleep on weekends to compensate [49]. Irregularity in sleeping schedule, independently of sleeping duration, was associated with obesity [50]. In addition, the circadian misalignment was linked to higher postprandial glucose and insulin levels, lower leptin levels [51] and a more pronounced insulin resistance and inflammatory profile [52]. By contrast, peripheral insulin sensitivity was found to be greater for MTs who also revealed decreased homeostatic model assessment of insulin resistance (HOMA-IR), adipose insulin resistance (Adipose-IR) and fasting insulin levels [53]. This finding is in correlation with other studies that revealed increased visceral fat and abdominal obesity in ETs compared to MTs [54,55].

The increased risk for developing metabolic disorders (metabolic syndrome, obesity, diabetes, etc.) in case of misalignment between internal and external chronotype has been well documented through the observation of parameters such as BMI and fat mass percentage. However, the measurement of markers related to skeletal muscle mass in association with chronotype alignment was mostly tackled by scientists interested in physical activity and performance, which will be discussed in a later section [56].

Skeletal muscle is a tissue that plays a central role in metabolic function, daily activity performance, and the prevention of many chronic diseases [57]. The importance of preserving muscle health is growing in the clinical field and has become a current challenge in combating various weight loss methods, which often involve a significant loss of muscle mass (25% to 29%) and strength [58], increasing the risk factors for morbidity and mortality in the older adult population.

The preservation of muscle health requires the integrated assessment of three fundamental domains: functional status, which reflects the normative development of muscle mass and strength; muscle performance, which evaluates the adequacy of muscle capacity to meet the demands of daily activities; and tissue composition, which provides insight into the efficiency of protein synthesis and the maintenance of muscle mass. The optimal development and maintenance of these domains is contingent upon overall muscle health, which is modulated by both external factors—such as nutritional intake, physical activity, and the temporal organization of daily behaviors—and internal factors, including endocrine regulation [59].

Skeletal muscle protein metabolism is regulated by mechanical, nutritional, and hormonal inputs. Testosterone and IGF-1 enhance anabolism through activation of the Akt/mTOR and PI3K/Akt/mTOR pathways, whereas cortisol promotes catabolism via protein degradation mechanisms [60]. Consequently, behavioral and lifestyle factors—including poor sleep quality, inadequate dietary intake, altered meal timing, sedentary behavior, and psychological stress—may compromise muscle health by impairing protein synthesis, ultimately reducing muscle function, composition, and performance [61].

Individual chronotype patterns may significantly influence muscle health and protein synthesis. For instance, the evening chronotype (ET) has been associated with lower levels of physical activity, greater sedentary time, poor sleep quality, insulin resistance, and increased risk of cardiovascular disease, all of which contribute to reduced muscle protein synthesis and loss of muscle mass [62,63,64]. Declines in muscle mass are typically accompanied by reductions in muscle strength, predisposing individuals to sarcopenia and frailty [65,66]. Moreover, muscle mass loss is closely linked to insulin resistance, metabolic syndrome, and age-related sarcopenia [67].

Sarcopenic obesity, defined in Section 1 of the Introduction, is a driver to find new strategies for weight loss, preventing decline in muscle mass and muscle strength [6]. The key to all strategies should be to maintain a healthy skeletal muscle turnover—the balance between muscle protein synthesis and muscle protein breakdown—through nutritional alterations, physical activity stimulation and hormonal regulations that promote protein synthesis [68].

Hormonal fluctuations are directly influenced by the internal body clock. Altered hormonal rhythms imply broad physiological and psychological actions, including effects on metabolism, glucose utilization, muscle mass and strength, adiposity, physical performance and well-being. People with different chronotypes, through their behaviors, could affect hormonal patterns and, hence, can impact health conditions [69,70]. For example, insulin sensitivity to glucose metabolism is lower in the afternoon, and consequently, when the highest caloric intake for ETs is in the afternoon or evening time, it results in a greater increase in plasma glucose and glucose intolerance compared to when the meal is in the morning [19].

Moreover, and besides the metabolic alterations leading to decreased glucose tolerance, eating late leads to a lower resting-energy expenditure and lower thermal effect of food, and finally, the usual cortisol fluctuations during a 24 h cycle are blunted [71].

Melatonin has been found to be at higher levels during the daytime of ETs. Such alterations of the melatonin secretion pattern can directly affect sleep quality, which is closely linked to health and performance. Poor sleep quality has effects on skeletal muscle homeostasis and glucose throughout the body that predispose people to various disease states, such as obesity, insulin resistance, and type 2 diabetes, and increased risk of all-cause mortality [72]. Endocrine function is greatly affected by poor sleep quality, causing alterations in the concentrations of appetite hormones such as leptin and ghrelin, which influence the feeling of hunger and satiety. In addition, the secretion of steroid hormones is affected by sleep, for example, increased plasma cortisol concentrations.

Conventionally, melatonin secretion has nocturnal peaks where it starts rapidly rising 2 to 3 h before sleep onset (evening) and rapidly falling in the morning [73,74]. There have been several studies that aimed at disrupting this pattern or showing differences in melatonin secretion under certain circumstances. Interrupting nighttime through light exposure has frequently been studied for its role in inhibiting melatonin secretion [75,76]. A shift in the sleep/wake cycle induced an increase in melatonin levels in the daytime [75]; in addition, short afternoon naps had the same effect of increased melatonin levels in the daytime [77]. Neuropathological disorders have been found to alter melatonin levels [78,79,80,81].

Cortisol is an important regulator of energy homeostasis. In response to stress in the form of perceived danger or acute inflammation, cortisol is released from the adrenal gland, rapidly mobilizing energy from glycogen, fat and proteins. In the case of inflammation, mobilization of proteins/amino acids is critical for the rapid synthesis of acute phase reactants and an efficient immune response to infection. While adaptive in response to infection, chronic mobilization can lead to a profound depletion of energy stores. Skeletal muscle represents the major body store of protein and can become substantially atrophied under conditions of chronic inflammation [82].

Furthermore, cortisol awakening response has been shown to peak around 30 min after waking up. This response varies between populations, influenced by light exposure, age, sex, health and stress. Evening-types do not demonstrate such a peak in cortisol levels in the first hour of being awake [82]. These alterations in the hormonal environment induced by lack of sleep can be a catalyst that sustains alterations in skeletal muscle metabolism by decreasing the rate of muscle protein synthesis resulting in a loss of muscle mass and muscle strength affecting functional outcomes [13].

Changes in hormonal secretion have been explained through studies that investigate the expression and regulatory roles of circadian genes. For example, in MTs, rising cortisol levels during the first hours of the day enhance the transcriptional activity of genes such as BMAL1 and PER2, aligning metabolic processes with the active phase of the day [20]. Conversely, the timing of food intake for the ETs, particularly when melatonin levels increase, disrupts the rhythmic expression of genes like CRY1 and PER1, impairing glucose tolerance and lipid handling. These feeding transitions actively reprogram gene expression in key metabolic tissues, reinforcing the role of nutrient timing as a modulator of circadian gene dynamics and overall metabolic homeostasis [83]. Similarly, groups exhibiting intermediate chronotype behavior, such as NTs, tend to display patterns more closely aligned with morning types than evening types, both in terms of dietary behavior and metabolic health, suggesting a more stable or less phase-delayed expression of genes such as BMAL1 and PER2 [84].

These differences related to metabolic response could be explained by the role of circadian clock genes in regulating energy homeostasis, given that, as mentioned previously, their expression patterns vary depending on the time of day. For instance, in white adipose tissue (WAT), transcriptional activity of the BMAL1/CLOCK complex, in a peripheral expression, governs key metabolic processes including lipogenesis, lipolysis, and β-oxidation, thereby influencing adipocyte proliferation and differentiation [85]. Consistent with this, studies in murine models have shown that deletion of Bmal1 disrupts the expression of central adipogenic regulators such as peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (Cebpα), leading to impaired adipose tissue functionality [86]. Along the same lines, a dysregulation at crosstalk levels has been described in mice, where an early nocturnal meal skipping—analogous to breakfast omission in humans—induces a misalignment of peripheral circadian clocks, promoting fat storage by the increase in lipogenic activity [87]. This study, by Yoshida et al. (2012), showed that mice subjected to early nocturnal fasting (ZT12–18) exhibited altered acrophases of core clock genes such as Bmal1, Per1, and Cry1 in liver and adipose tissue accompanied by upregulation of lipogenesis-related genes including Sterol Regulatory Element-Binding Protein 1c (Srebp-1c) and Fatty Acid Synthase (Fasn), despite an isocaloric intake [87].

The total energy balance and the associated alterations in body weight are not components of a straightforward simple equation. For example, several studies have demonstrated that high-fat diet protocols induce a weakened diurnal rhythm and an extended circadian cycle, mechanisms that ultimately contribute to insulin resistance, local inflammation, and a disruption in the secretion balance of adipokines, such as leptin and adiponectin [91,92]. Nutritional and health status is complex; many factors interact, such as hunger, satiety, food availability and consumption, the environment and social factors. The energy consumed is not solely defined by the quality and quantity of the meal. There is a new focus on nutritional chronotype: the time at which the food is consumed and its nutritional value in accordance with other physiological indicators such as sleep and physical activity. For further clarification, nutritional chronotype is marked by the frequency, time of the meal (beginning and end), its nutritional value, the regularity and the scheduling of the daily intake in relation to the events of daily life such as work, exercise, leisure, sleep and social relationships, among others [93]. Several studies have mentioned metabolic health benefits—primarily determined by body weight, BMI, and body composition—in case of alignment between the external clock and the internal clock [38]. Hence, it has been shown that alignment between the external clock—translated as the timing of the highest caloric meal consumed—and the internal clock—translated as the individual's chronotype—is associated with decreased BMI and fat mass index (FMI) along with increased fat-free mass index (FFMI) [38].

So, switching the time of meal consumption, most importantly the highest caloric meal consumption, to earlier in the day could positively affect metabolic health. These actions should respect the typical insulin fluctuation in a 24 h cycle in order to enhance insulin sensitivity, leading to a better tolerance to glucose.

It has been established that certain hormones enhance protein synthesis by activating anabolic signaling pathways or by suppressing the expression of genes associated with protein degradation [60]. Experimental evidence further suggests that behavioral patterns such as changes in sleep duration can significantly influence muscle metabolism by directly interacting with the expression and function of the circadian clock [8].

Sleep is essential for muscle health, yet it is increasingly disrupted in modern society due to 24 h exposure to artificial light, unrestricted access to energy-dense snacks, social engagements, and low levels of physical activity. These factors interfere with normal circadian rhythms, carrying profound implications for various physiological and metabolic processes.

Sleep restriction impairs skeletal muscle glucose homeostasis and alters the regulation of appetite-related hormones such as ghrelin and leptin. Additionally, sleep deprivation leads to elevated secretion of steroid hormones, notably increasing plasma cortisol concentrations. These hormonal disturbances may act as catalysts for impaired skeletal muscle metabolism, resulting in decreased rates of muscle protein synthesis, loss of lean mass, and concomitant reductions in muscle strength and functional capacity [85].

Consistent, high-quality sleep is essential for optimal muscle synthesis and recovery, as deep sleep stages—particularly slow-wave sleep—trigger the release of growth hormone, which stimulates muscle protein synthesis and tissue repair. Several studies show that sleep deprivation impairs anabolic signaling (e.g., mTOR), reduces testosterone, elevates cortisol, and alters muscle gene expression, all of which hinder muscle growth and increase protein breakdown. To support muscle health, adults should maintain a regular sleep–wake schedule, avoid late-night training and screen exposure, and consume protein-rich meals earlier in the evening to enhance overnight recovery [13,90].

Exercise plays a pivotal role in modulating circadian rhythms and chronotype-related health outcomes and also plays a key role in stimulating muscle protein synthesis, promoting hypertrophy, and enhancing adaptation to physical stress. Resistance training, in particular, contributes significantly to increases in both muscle mass and strength, thereby supporting overall muscle health, while aerobic and high-intensity interval training improve sleep quality and facilitate circadian adjustment under disrupted light/dark schedules. Notably, engagement in regular physical activity during midlife has been associated with a reduced risk of sarcopenia and serves as a positive predictor of muscular strength and physical performance in older age [94]. Time of exercise, particularly in the midday–afternoon or evening, is consistently associated with cardiovascular benefits, including reductions in blood pressure, heart rate, and cardiometabolic risk. Moreover, exercise enhances glucose and lipid metabolism, increases insulin sensitivity, and mitigates metabolic disease risk, partly through its regulatory effects on circadian rhythms [21].

Resistance training enhances muscle size, strength, and metabolic capacity through mechanical loading and intracellular signaling pathways. Skeletal muscle functions as a circadian tissue, with clock components and systemic hormonal rhythms modulating metabolism, protein synthesis, and exercise responsiveness. Training outcomes vary by time of day: evening sessions favor hypertrophy and anabolic signaling via pathways like ribosomal biogenesis and mTOR, while morning sessions enhance mitochondrial and autophagy-related pathways. These findings highlight the importance of exercise timing and support incorporating chronobiological principles into training prescriptions to optimize muscle adaptation and individualized strategies [95,96].

At the molecular level during exercise, some modulators of energy homeostasis, such as AMPK, are overexpressed and regulate the expression of PER and CRY, thereby directly influencing metabolic processes and hormonal responses that impact exercise performance [97]. Furthermore, the role of PER2 extends beyond circadian regulation and has been implicated in the modulation (inhibition) of the mammalian target of rapamycin complex 1 (mTORC1), a central regulator of protein synthesis and glucose and lipid metabolism [98]. PER2 directly promotes the recruitment of the protein hamartin (TSC1) to the mTORC1 complex, thereby inhibiting its activity. Consequently, beyond its canonical role in the circadian cycle, PER2 has emerged as a key determinant of exercise physiology and performance [99]. Regarding the interaction between other circadian clock genes, it has been described how BMAL1 modulates mTORC1 activity too. BMAL1 knockout in mouse models reveals mTORC1 hyperactivation through enhanced phosphorylation of downstream targets such as Ribosomal Protein S6 Kinase Beta-1 (S6K1) and Eukaryotic Translation Initiation Factor 4E-Binding Protein 1 (4EBP1), highlighting the negative regulatory role exerted by BMAL1 on this signaling pathway [100].