“Blood of youth” to rejuvenate the muscles?

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Aging is associated with a significant decrease in muscle mass (called sarcopenia), general muscle performance, and severe fatigue. In a new study, researchers from UPMC and the University of Pittsburgh identified an important mediator of young muscles in mice. A discovery that could advance muscle regeneration therapies for the elderly.

Published in the journal Nature Aging, the study shows that circulating shuttles, called extracellular vesicles, transmit genetic instructions to muscle cells that encode the “anti-aging” protein Klotho. The loss of muscle function and poor muscle repair in older mice are believed to be due to aging of their extracellular vesicles, which carry fewer copies of these genetic instructions than those in young animals.

These results represent an important advance in understanding why the ability of muscles to regenerate decreases with age. “It helps us understand the basic biology of how muscle regeneration works and its failure during aging,” study co-author Fabrisia Ambrosio, director of rehabilitation at UPMC International and associate professor of physical medicine and rehabilitation at Pitt, said in a statement. . “Then, taking this information to the next step, we can think about using extracellular vesicles as a therapy to counteract these age-related defects.”

Decades of research on aging

This new study is based on decades of research showing that when older mice are fed blood from young mice, many cells and tissues revert to their youthful characteristics. In 2019, researchers from the Pasteur Institute and the CNRS had elucidated the properties of the GDF11 molecule, present in the blood. Before this study, the role of GDF11 in aging was controversial.

By injecting GDF11, from the GDF (Growth Differentiation Factor) family of proteins, into aging mouse models, the researchers noted an increase in neurogenesis (the formation of new neurons) and the shape of blood vessels. The system used, called “heterochronic parabiosis”, consists of continuously connecting the blood flow between two mice, one young and one old.

Extracellular vesicles: mediators of muscle regeneration

With this new study, the researchers focused on extracellular vesicles, as their circulation between cells through blood and other body fluids was an interesting advantage in muscle regeneration. Extracellular vesicles are used to send information to target cells.

Ambrosio and his team took serum, the fraction of blood that remains after removing blood cells and clotting factors, from young mice and injected it into elderly mice with injured muscles. The mice that received young serum showed greater muscle regeneration and functional recovery compared to those that received the placebo treatment.

However, the restorative properties of the serum disappeared when the extracellular vesicles were removed, demonstrating that these vesicles mediate the beneficial effects of young blood. Researchers have discovered that extracellular vesicles transmit genetic instructions (or mRNA) that encode the Klotho protein to muscle progenitor cells. It is a type of stem cell that is important for the regeneration of skeletal muscles.

Extracellular vesicles taken from aged mice contained fewer copies of Klotho mRNA than those from young mice. In previous work, Ambrosio and his team have shown that Klotho is an important regulator of the regenerative capacity of muscle progenitor cells and that this protein decreases with age.

The new study shows for the first time that age-related changes contribute to Klotho depletion in aging stem cells. Extracellular vesicles that provide mRNA encoding the protein could be developed into new therapies to aid muscle regeneration in the elderly and improve functional recovery after injury.

In addition to muscles, extracellular vesicles may also help reverse other effects of aging. Two study researchers just received a grant to explore the potential of extracellular vesicles to reverse age-related decline in cognition.

Nature Aging

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