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No pain no gain: the old formula for muscle stem regeneration does not lie

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, according to many scientific publications. There’s a lot of interest in understanding how exercise confers these health benefits. No matter what type of sport it is, everyone can choose his or her own, but physical motion ignites the pathways of signal and metabolism that can confer health to practically every district or organ of our body. According to a new study by researchers at Stanford School of Medicine, a nightly jaunt on the exercise wheel enhances muscle-repair capabilities in old mice. Only older mice saw this benefit, which the researchers found is due to the rejuvenation of the animals’ muscle stem cells. The researchers also identified a molecular pathway involved in turning back the clock on the cells. Drugs that manipulate the pathway might be an effective substitute for exercise, they suggest. Thomas Rando, MD, PhD, professor of Neurology and director of Stanford’s Glenn Center for the Biology of Aging, is the senior author of the study, which will be published April 13 in Nature Metabolism. Medical student Jamie Brett, PhD, postdoctoral scholar Marina Arjona, PhD, and visiting scholar Mika Ikeda, PhD, are the lead authors.

Dr Rando revealed his shock for the discovery: “Studies conducted by us and others have shown that tissue regeneration decreases with age, and that this is due to declining function in adult stem cells. Many researchers are looking for a way to restore youthfulness. But the effect in old animals is very significant. 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”. Unlike embryonic or induced pluripotent stem cells, which can give rise to any tissue in the body, tissue-specific stem cells are restricted in their potential. Muscle stem cells wait in the wings along the muscle fibers in a resting state known as quiescence until called upon to repair damage. While no researchers have discovered a reliable fountain of youth, it’s well known that certain lifestyle adjustments can be beneficial. In particular, the researchers wanted to know whether and how voluntary exercise affects the function of muscle stem cells in mice. They gave mice that were about 20 months old, the equivalent of being 60-70 years old in humans, and mice that were 3 to 4 months old, the equivalent of 20- to 30-year-old humans, access to an exercise wheel and allowed them to run at will (no restrictions).

Young mice averaged about 10 kilometers each night, and the older mice covered about 5 kilometers. Two other groups of young and old mice were given wheels that didn’t rotate to serve as controls. The animals were exercising at the intensity levels at which they were comfortable, 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. Subsequent analysis showed that the muscle stem cells of the exercising animals remained quiescent, and that the animals did not develop significant numbers of new muscle fibers in response to the exercise. After three weeks of nightly aerobics for the active groups, the researchers compared the ability of the animals to repair muscle damage. They found that, as expected, the aged, sedentary mice were significantly less able to repair muscle damage than younger sedentary mice. However, the older animals that had exercised regularly were significantly better at repairing muscle damage than were their counterparts that did not exercise. This exercise benefit was not observed in the younger animals.

Similar results were obtained when muscle stem cells from older mice that had exercised were transplanted into younger mice. The stem cells from the exercising animals contributed more to the repair process than did those from their sedentary peers. The researchers also showed that injecting blood from an old mouse that had exercised into an old mouse that hadn’t conferred a similar benefit in stem cell function, suggesting that exercise simulates the production of some factors that then circulate in the blood and enhance the function of older stem cells. Dr Rando is fascinated by this result, noting that the result mirrors those from earlier studies jointly conducted by him and Tony Wyss-Coray, PhD, a professor of Neurology at the School of Medicine, indicating that blood from a young mouse appears to somehow enhance the tissue-specific stem cells in an older animal. Further studies indicated that the exercise-induced rejuvenation observed by the researchers could be mimicked by increasing the expression of a signaling molecule called cyclin D1. This protein is a cofactor of some protein kinases called cyclin-dependet kinases (CDKs), that are involved in cellular proliferation and differentiation. In particluar, CDK2 and CDK4 use cyclin D1 to maintain “stemness” and the replicative potential in most stem cells, including those from muscle (satellite cells).

According to Dr. Rando, the discovery suggests that it may one day be possible to artificially activate this pathway to keep aging muscle stem cells functioning at their youthful best.

  • edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Sarkar TJ et al., Rando TA, Sebastiano V. Nat Commun 2020; 11(1):1545.

Tawfik VL et al., Rando TA, Clark JD. J Physiol 2020 Jan; 598(2):317-329. 

van Velthoven CTJ, Rando TA. Cell Stem Cell 2019 Feb 7; 24(2):213-225.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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