Tag: muscle injury

Time of Injury Matters: Circadian Rhythms Affect Muscle Repair

Photo by Mat Napo on Unsplash

Circadian rhythms doesn’t just dictate when we sleep — it also determines how quickly our muscles heal. A new Northwestern Medicine 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 Clara Peek, assistant professor of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine.

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,” Peek 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 behaviour, metabolism, body temperature and hormones — all these are circadian.”

How the study was conducted

Previous research from the Peek 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, Peek and her collaborators sought to better understand how circadian clocks within muscle stem cells govern regeneration depending on the time of day.

For the study, Peek and her collaborators 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’ signalling to each other was much stronger right after injury when mice were injured during their wake period,” Peek 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.  

Why it matters

The findings may be especially relevant to understanding the circadian rhythm disruptions that occur in aging and obesity, Peek said.

“Circadian disruptions linked to aging and metabolic syndromes like obesity and diabetes are also associated with diminished muscle regeneration,” Peek 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?”

What’s next

Moving forward, Peek and her collaborators 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,” Peek 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.”

Source: Northwestern University

Massage Heals Injured Muscle by Getting Immune Cells Out

Photo by Andrea Piacquadio from Pexels

While massage has been used to treat muscle pain and injury for thousands of years, it is only now that a study has scientifically confirmed that it improves recovery and strength gains. Intriguingly, the mechanism behind this is mechanically clearing out of immune cells from the injury site after they have done their job.

Using a custom-designed robotic system massage system for mice, the team found that this mechanical loading (ML) rapidly clears immune cells called neutrophils out of severely injured muscle tissue. This process also removed inflammatory cytokines released by neutrophils from the muscles, enhancing the process of muscle fiber regeneration. The research is published in Science Translational Medicine.

“Lots of people have been trying to study the beneficial effects of massage and other mechanotherapies on the body, but up to this point it hadn’t been done in a systematic, reproducible way. Our work shows a very clear connection between mechanical stimulation and immune function. This has promise for regenerating a wide variety of tissues including bone, tendon, hair, and skin, and can also be used in patients with diseases that prevent the use of drug-based interventions,” said first author Bo Ri Seo, PhD.

Dr Seo and her colleagues previously found in mouse studies that mechanical massage of injured muscles doubled the rate of muscle regeneration and reduced tissue scarring over the course of two weeks. With a new device inspired by soft robotics, the researchers sought to confirm these results. They found that the greater the force applied, the stronger the injured muscles became.

In vitro experiments suggested that neutrophil-secreted factors stimulate the growth of muscle cells, but the prolonged presence of those factors impairs the production of new muscle fibres. In vivo testing showed that stronger muscle fibre types predominated in treated, injured muscle types. Depleting neutrophils in mice after the third day resulted in greater strength recovery, indicating that they are important in the initial recovery period but removing them from the injury site early leads to improved muscle regeneration.

“The idea that mechanics influence cell and tissue function was ridiculed until the last few decades, and while scientists have made great strides in establishing acceptance of this fact, we still know very little about how that process actually works at the organ level. This research has revealed a previously unknown type of interplay between mechanobiology and immunology that is critical for muscle tissue healing, in addition to describing a new form of mechanotherapy that potentially could be as potent as chemical or gene therapies, but much simpler and less invasive,” said Don Ingber, MD, PhD, founding director of the Wyss Institute for Biologically Inspired Engineering at Harvard.

Source: Wyss Institute for Biologically Inspired Engineering at Harvard