Circadian rhythms affect muscle repair
The body’s internal clock doesn’t just dictate when we sleep — it also determines how quickly our muscles heal.
A new study in mice, published in Science Advances, suggests that muscle injuries heal faster when they occur during the body’s natural waking hours.
The findings could have implications for shift workers and may also prove useful in understanding the effects of aging and obesity, said senior author.
The study also may help explain how disruptions like jetlag and daylight saving time changes impact circadian rhythms and muscle recovery.
“In each of our cells, we have genes that form the molecular circadian clock,” the author said. “These clock genes encode a set of transcription factors that regulate many processes throughout the body and align them with the appropriate time of day. Things like sleep/wake behavior, metabolism, body temperature and hormones — all these are circadian.”
Previous research from the laboratory found that mice regenerated muscle tissues faster when the damage occurred during their normal waking hours. When mice experienced muscle damage during their usual sleeping hours, healing was slowed.
In the current study, the researchers sought to better understand how circadian clocks within muscle stem cells govern regeneration depending on the time of day.
For the study, the authors performed single-cell sequencing of injured and uninjured muscles in mice at different times of the day. They found that the time of day influenced inflammatory response levels in stem cells, which signal to neutrophils — the “first responder” innate immune cells in muscle regeneration.
“We discovered that the cells’ signaling to each other was much stronger right after injury when mice were injured during their wake period,” the author said. “That was an exciting finding and is further evidence that the circadian regulation of muscle regeneration is dictated by this stem cell-immune cell crosstalk.”
The scientists found that the muscle stem cell clock also affected the post-injury production of NAD+, a coenzyme found in all cells that is essential to creating energy in the body and is involved in hundreds of metabolic processes.
Next, using a genetically manipulated mouse model, which boosted NAD+ production specifically in muscle stem cells, the team of scientists found that NAD+ induces inflammatory responses and neutrophil recruitment, promoting muscle regeneration.
The findings may be especially relevant to understanding the circadian rhythm disruptions that occur in aging and obesity, the author said.
“Circadian disruptions linked to aging and metabolic syndromes like obesity and diabetes are also associated with diminished muscle regeneration,” the author said. “Now, we are able to ask: do these circadian disruptions contribute to poorer muscle regeneration capacity in these conditions? How does that interact with the immune system?”
Moving forward, the researchers hope to identify exactly how NAD+ induces immune responses and how these responses are altered in disease.
“A lot of circadian biology focuses on molecular clocks in individual cell types and in the absence of stress,” the author said. “We haven't had the technology to sufficiently look at cell-cell interactions until recently. Trying to understand how different circadian clocks interact in conditions of stress and regeneration, is really an exciting new frontier.”
https://www.science.org/doi/10.1126/sciadv.adq8538
https://sciencemission.com/stem-cell-circadian-clock-in-muscle-repair
