The body’s internal clock not only determines when we sleep, but also how quickly our muscles heal. A new study of mice by Northwestern Medicine, 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 also prove useful in understanding the effects of aging and obesity, according to lead author Clara Peek, an assistant professor of biochemistry and molecular genetics at the Feinberg School of Medicine at Northwestern University. The study may also help explain how disruptions such as jet lag and the switch to daylight saving time affect circadian rhythm and muscle recovery.

Circadian Rhythms and Muscle Recovery

“In each of our cells, we have genes that form the molecular circadian clock,” Peek said. “These clock genes encode a suite of transcription factors that regulate many processes throughout the body, timing them to occur at the appropriate time of day. Things like sleep/wake behavior, metabolism, body temperature, and hormones—it’s all circadian.” Previous research from the Peek lab found that mice regenerate muscle tissue more quickly when damage occurs during their normal waking hours. When mice sustained muscle damage during their usual sleeping hours, healing slowed. In the current study, Peek and her collaborators sought to better understand how the circadian clocks in muscle stem cells control regeneration depending on the time of day.

For the study, Peek and her co-workers 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 the inflammatory response in the stem cells, which signal neutrophils – the “first responders” among the innate immune cells in muscle regeneration. The researchers found that the signals between cells were much stronger immediately after injury when mice were injured during their waking hours. This was an exciting finding and further evidence that the circadian regulation of muscle regeneration is controlled by this dialog between stem cells and immune cells. The scientists found that the muscle stem cell clock also influenced NAD⁺ production after injury. NAD⁺ is a coenzyme found in all cells that is essential for energy production in the body and is involved in hundreds of metabolic processes. Next, the team of scientists used a genetically modified mouse model that specifically increased NAD⁺ production in muscle stem cells and found that NAD⁺ induces inflammatory responses and the recruitment of neutrophils, thus promoting muscle regeneration.

Exciting Field of Research

According to the researchers, the results could be particularly relevant for understanding the circadian rhythm disorders associated with ageing and obesity. Circadian disorders associated with ageing and metabolic syndromes such as obesity and diabetes are also associated with reduced muscle regeneration. Now, the experts say, we can ask the questions: Do these circadian disruptions contribute to poorer muscle regenerative capacity in these conditions? How does this affect the immune system?

In the future, Peek and her collaborators hope to determine exactly how NAD⁺ triggers immune responses and how these responses are altered in disease. Much of circadian biology focuses on molecular clocks in single cell types and in the absence of stress. Until recently, researchers did not have the technology to adequately study cell-cell interactions. Understanding how different circadian clocks interact under conditions of stress and regeneration is truly an exciting new frontier.