Muscle cells contain their own circadian clocks and disrupting them with shift work can have a profound impact on aging, according to the results of a preclinical study carried out by Jeffrey Kelu, PhD, and Simon Hughes, PhD, at the Randall Centre for Cell and Molecular Biophysics, King’s College London.
The researchers’ work in zebrafish revealed how muscle cells have an intrinsic timekeeping mechanism that regulates protein turnover, modulating muscle growth and function. At night, the muscle clock activates the breakdown of defective proteins, replenishing muscles while the body rests. Altering this intrinsic muscle clock was associated with muscle decline seen with age, known as sarcopenia. The findings imply that disrupting circadian rhythms, as with shift work, accelerates the aging process.
The team says the results of their study contribute to the growing evidence of the damage that shift work has on health. Kelu commented, “In the UK, approximately four million shift workers play a vital role in keeping businesses and emergency services operational around the clock. Our study provides further evidence that the disruption of circadian rhythms in shift workers compromises multiple aspects of health. Understanding how circadian disruption contributes to sarcopenia is essential for developing strategies to improve the health and wellbeing of shift workers.”
The researchers reported on their findings in PNAS, in a paper titled “Muscle peripheral circadian clock drives nocturnal protein degradation via raised Ror/Rev-erb balance and prevents premature sarcopenia.” In their report Kelu and Hughes concluded, “… we establish a role of the muscle peripheral clock in the regulation of muscle protein degradation, further understanding of which may help mitigate the loss of muscle strength and mass that is associated with circadian disruptions resulted from sleep deprivation, nightshift, travel, and aging.”
Weakening circadian rhythms in older people are associated with worse aging prognosis, “… suggesting that intrinsic circadian clocks promote longevity,” the authors wrote. And in model organisms, disrupting transcriptional circadian clock leads to premature aging. Furthermore, they stated, “Circadian disruption, occurring in shift work, sleep deprivation, or dementia, increases the risk of sarcopenia, the age-related loss of muscle mass and strength.”
For their newly reported research the team turned to zebrafish, a model organism often used in biological studies. Zebrafish share up to 70% of genes with humans, which are easy to modify in the laboratory, and they are transparent, so their muscles are easily observed under a microscope.
The team had previously reported that zebrafish display circadian variation in muscle growth rate, “even in the absence of physical activity and feeding.” Commenting on their newly reported study, Kings College research associate Kelu, stated, “To investigate the impact of circadian disruption on muscle cells, we impaired the muscle clock function in zebrafish by overexpressing a malfunctioning clock protein.” The researchers then monitored the fish for two years, comparing them to healthy controls.
Kelu added, “While no significant differences in muscle size were observed at younger ages—six months and one year—fish lacking a functional muscle clock showed clear signs of premature aging at two years. They were shorter, weighed less, swam less frequently and at slower speeds. These are hallmarks of sarcopenia and overall decline in mobility, which has been reported in shift workers.”
![Muscle membranes fluorescently labelled in zebrafish, allowing measurement of muscle size [King's College London]](https://www.genengnews.com/wp-content/uploads/2025/05/low-res-1-182x300.webp "Muscle membranes fluorescently labelled in zebrafish, allowing measurement of muscle size [King's College London]")
Muscle membranes fluorescently labelled in zebrafish, allowing measurement of muscle size [King’s College London]
To help understand the mechanism underlying their observations, the researchers investigated protein turnover, a process essential for maintaining muscle mass, often impaired with aging. They showed that during rest at night, the muscle clock regulated the degradation of defective muscle proteins, which accumulate throughout the day due to usage. The study showed that this ‘nocturnal clearance’ is essential for preserving muscle function. “… we show that the ubiquitin–proteasome system (UPS) and autophagy, which mediate muscle protein degradation, are each upregulated at night under the control of the muscle peripheral clock,” they wrote. Further experiments showed that Ror and Rev-erb, two important components of the muscle peripheral clock, are crucial for regulating nocturnal protein clearance via the ubiquitin–proteasome system and autophagy. “In animals lacking a functional muscle clock, Ror and Rev-erb imbalances lead to altered circadian muscle growth and reduced muscle function,” the team further noted.
So, the accumulation of defective proteins may drive the accelerated muscle decline observed in aged fish with a dysfunctional muscle clock and in shift workers. “Our findings highlight the possibility of using circadian biology to develop treatments aimed at preventing muscle decline in shift workers,” Kelu stated. “Preclinical studies using drugs to modulate specific clock proteins are currently underway. This paves the way for future therapies that could improve aging in shift workers.”
In their paper the authors stated, “As disease conditions often manifest in a time-dependent manner, and likewise kinetics of medications vary according to circadian rhythmicity, our work may contribute to the development of chronomedicine to treat debilitating muscle conditions with temporal precision to benefit patients.”
Co-author Hughes, an expert in developmental cell biology, added, “This work shows how studying something as complicated as muscle growth in a simple system, like little fish larva, can really teach us something. Of course, someone then has to check if it’s also true in people—but at least the fish show us where to look.”
The post Muscle’s Circadian Clock Regulates Protein Degradation in Zebrafish, May Lead to Treatments appeared first on GEN - Genetic Engineering and Biotechnology News.
The researchers’ work in zebrafish revealed how muscle cells have an intrinsic timekeeping mechanism that regulates protein turnover, modulating muscle growth and function. At night, the muscle clock activates the breakdown of defective proteins, replenishing muscles while the body rests. Altering this intrinsic muscle clock was associated with muscle decline seen with age, known as sarcopenia. The findings imply that disrupting circadian rhythms, as with shift work, accelerates the aging process.
The team says the results of their study contribute to the growing evidence of the damage that shift work has on health. Kelu commented, “In the UK, approximately four million shift workers play a vital role in keeping businesses and emergency services operational around the clock. Our study provides further evidence that the disruption of circadian rhythms in shift workers compromises multiple aspects of health. Understanding how circadian disruption contributes to sarcopenia is essential for developing strategies to improve the health and wellbeing of shift workers.”
The researchers reported on their findings in PNAS, in a paper titled “Muscle peripheral circadian clock drives nocturnal protein degradation via raised Ror/Rev-erb balance and prevents premature sarcopenia.” In their report Kelu and Hughes concluded, “… we establish a role of the muscle peripheral clock in the regulation of muscle protein degradation, further understanding of which may help mitigate the loss of muscle strength and mass that is associated with circadian disruptions resulted from sleep deprivation, nightshift, travel, and aging.”
Weakening circadian rhythms in older people are associated with worse aging prognosis, “… suggesting that intrinsic circadian clocks promote longevity,” the authors wrote. And in model organisms, disrupting transcriptional circadian clock leads to premature aging. Furthermore, they stated, “Circadian disruption, occurring in shift work, sleep deprivation, or dementia, increases the risk of sarcopenia, the age-related loss of muscle mass and strength.”
For their newly reported research the team turned to zebrafish, a model organism often used in biological studies. Zebrafish share up to 70% of genes with humans, which are easy to modify in the laboratory, and they are transparent, so their muscles are easily observed under a microscope.
The team had previously reported that zebrafish display circadian variation in muscle growth rate, “even in the absence of physical activity and feeding.” Commenting on their newly reported study, Kings College research associate Kelu, stated, “To investigate the impact of circadian disruption on muscle cells, we impaired the muscle clock function in zebrafish by overexpressing a malfunctioning clock protein.” The researchers then monitored the fish for two years, comparing them to healthy controls.
Kelu added, “While no significant differences in muscle size were observed at younger ages—six months and one year—fish lacking a functional muscle clock showed clear signs of premature aging at two years. They were shorter, weighed less, swam less frequently and at slower speeds. These are hallmarks of sarcopenia and overall decline in mobility, which has been reported in shift workers.”
Muscle membranes fluorescently labelled in zebrafish, allowing measurement of muscle size [King’s College London]
To help understand the mechanism underlying their observations, the researchers investigated protein turnover, a process essential for maintaining muscle mass, often impaired with aging. They showed that during rest at night, the muscle clock regulated the degradation of defective muscle proteins, which accumulate throughout the day due to usage. The study showed that this ‘nocturnal clearance’ is essential for preserving muscle function. “… we show that the ubiquitin–proteasome system (UPS) and autophagy, which mediate muscle protein degradation, are each upregulated at night under the control of the muscle peripheral clock,” they wrote. Further experiments showed that Ror and Rev-erb, two important components of the muscle peripheral clock, are crucial for regulating nocturnal protein clearance via the ubiquitin–proteasome system and autophagy. “In animals lacking a functional muscle clock, Ror and Rev-erb imbalances lead to altered circadian muscle growth and reduced muscle function,” the team further noted.
So, the accumulation of defective proteins may drive the accelerated muscle decline observed in aged fish with a dysfunctional muscle clock and in shift workers. “Our findings highlight the possibility of using circadian biology to develop treatments aimed at preventing muscle decline in shift workers,” Kelu stated. “Preclinical studies using drugs to modulate specific clock proteins are currently underway. This paves the way for future therapies that could improve aging in shift workers.”
In their paper the authors stated, “As disease conditions often manifest in a time-dependent manner, and likewise kinetics of medications vary according to circadian rhythmicity, our work may contribute to the development of chronomedicine to treat debilitating muscle conditions with temporal precision to benefit patients.”
Co-author Hughes, an expert in developmental cell biology, added, “This work shows how studying something as complicated as muscle growth in a simple system, like little fish larva, can really teach us something. Of course, someone then has to check if it’s also true in people—but at least the fish show us where to look.”
The post Muscle’s Circadian Clock Regulates Protein Degradation in Zebrafish, May Lead to Treatments appeared first on GEN - Genetic Engineering and Biotechnology News.