Summary: Older mice that ran voluntarily showed markedly improved muscle repair. The study suggests that regular, moderate exercise can rejuvenate muscle stem cells and restore more youthful tissue-repair capacity.
Source: Stanford
A nightly run on a wheel improves muscle repair in aged mice, according to a new Stanford School of Medicine study.
Researchers found that voluntary, low-stress exercise restored the function of muscle stem cells in old mice, enabling more efficient regeneration after injury. The benefit was specific to older animals and appears to come from molecular changes that make aged stem cells behave more like those in young animals.
“The effect in old animals is very significant,” said Thomas Rando, MD, PhD, professor of neurology and neurological sciences and director of Stanford’s Glenn Center for the Biology of Aging. “We found that regular exercise restores youthfulness to tissue repair. Their muscle stem cells start to look and behave like those of much younger animals.”
The team also identified a signaling pathway that helps explain how exercise reverses age-related decline in these cells. Manipulating that pathway with drugs might one day reproduce some of exercise’s rejuvenating effects.
The study will be published April 13 in Nature Metabolism. Lead authors include medical student Jamie Brett, PhD; postdoctoral scholar Marina Arjona, PhD; and visiting scholar Mika Ikeda, PhD, with Rando as senior author.
Muscle repair depends on a population of tissue-specific stem cells that remain dormant along muscle fibers until they are needed. These muscle stem cells, or MuSCs, sit in a resting state called quiescence and are activated to rebuild damaged tissue. While embryonic or induced pluripotent stem cells can become many tissue types, MuSCs are committed to maintaining and repairing skeletal muscle.
Benefits of lifestyle adjustments
Aging reduces the ability of tissue-specific stem cells to regenerate damaged tissue. Many researchers are looking for ways to restore youthful function to these cells, and lifestyle measures such as exercise are long associated with better healthspan. “Exercise is known to reduce the risk of a wide variety of age-related problems, including cardiovascular disease, cancer and perhaps even Alzheimer’s disease,” Rando said. “There’s a lot of interest in understanding how exercise confers these health benefits.”
To test whether voluntary exercise improves MuSC function, the team gave mice access to running wheels. Older mice (about 20 months, roughly equivalent to 60–70 human years) and young adult mice (3–4 months, roughly 20–30 human years) were allowed to run at will each night. Young mice averaged about 10 kilometers per night, while older mice ran around 5 kilometers. Control groups of young and old mice had wheels that did not rotate.
“The animals were exercising at the intensity levels at which they were comfortable,” Rando said, “much like what people do for their own health. This is a less stressful situation than resistance training or intense endurance exercise, which may themselves affect muscle stem cell function.” Analysis showed the stem cells of exercising mice remained quiescent between sessions and that exercise alone did not produce large numbers of new muscle fibers.
After three weeks of nightly voluntary running, researchers injured a small region of muscle to assess repair. As expected, aged sedentary mice regenerated more poorly than young sedentary mice. But aged mice that had exercised repaired muscle far better than their sedentary peers. That improvement was specific to old mice; young animals showed no comparable benefit from this level of voluntary running.
To test whether the effect was intrinsic to the stem cells, investigators transplanted MuSCs from exercised old mice into younger hosts. The transplanted cells from exercised donors contributed more effectively to repair than cells from sedentary old donors, indicating exercise produced cell-autonomous improvements in aged MuSCs.
Benefit of young blood
The team also found that transferring blood from an exercised old mouse into a sedentary old mouse improved the recipient’s stem-cell function. That result suggests exercise triggers production of circulating factors that rejuvenate aged MuSCs, echoing earlier work showing young blood can enhance tissue-specific stem-cell activity in older animals. “That’s really fascinating,” Rando said.
Further experiments implicated the cell-cycle regulator cyclin D1 in the rejuvenation process. Cyclin D1 expression declines with age in MuSCs, and increasing its levels in old stem cells restored their activation capacity. Mechanistic studies indicated cyclin D1 supports MuSC activation at least in part by repressing TGF-β signaling. These findings raise the possibility that pharmacologic activation of this pathway could mimic exercise’s benefits for aging muscle.
“If we could develop a drug that mimics this effect, we may be able to experience the benefit without having to do months of exercise,” Rando said.
Other Stanford co-authors include Tony Wyss-Coray; Antoine de Morree, PhD; Daniel Benjamin, PhD; Cristina Rodriguez-Mateo, PhD; Ingrid Egner, PhD; Luiz Perandini, PhD; Heather Ishak; Armon Goshayeshi; Pieter Both; and Michael Betley.
Funding: The research was supported by Stanford’s Medical Science Training Program, the California Institute for Regenerative Medicine, the National Institutes of Health (grants TR01AG047820, P01AG036695, R37AG023806 and R01AR062185), the Glenn Foundation for Medical Research and the Department of Veterans Affairs.
About this neuroscience research article
Source: Stanford
Media Contacts: Krista Conger – Stanford
Image Source: The image is in the public domain.
Original Research: “Exercise rejuvenates quiescent skeletal muscle stem cells in old mice through restoration of Cyclin D1” by Jamie O. Brett, Marina Arjona, Mika Ikeda, Marco Quarta, Antoine de Morrée, Ingrid M. Egner, Luiz A. Perandini, Heather D. Ishak, Armon Goshayeshi, Daniel I. Benjamin, Pieter Both, Cristina Rodríguez-Mateo, Michael J. Betley, Tony Wyss-Coray & Thomas A. Rando. Nature Metabolism. DOI: 10.1038/s42255-020-0190-0.
Abstract
Age impairs tissue repair, especially in skeletal muscle, where muscle stem cells (MuSCs) regenerate tissue efficiently in young adults but poorly in older organisms. Although aged MuSCs show functional decline, they can be rejuvenated by interventions that improve the systemic environment. This study shows that voluntary wheel running accelerates muscle repair in old mice and enhances old MuSC function. Transcriptional profiling and genetic experiments reveal that restoration of MuSC activation depends on cyclin D1, whose expression decreases with age. Pharmacologic work suggests cyclin D1 preserves activation capacity by repressing TGF-β signaling. Overall, voluntary exercise emerges as a practical strategy to rejuvenate aged muscle stem cells and highlights a specific role for cyclin D1 in stem-cell quiescence.
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