Study Identifies Factor in ‘Young Blood’ That Helps Rejuvenate Muscle in Aged Mice

As we age, our muscles gradually become smaller, weaker, and less able to heal after injury. In a new study, researchers at UPMC and the University of Pittsburgh have identified an important mediator of youth in mouse muscle, a finding that may advance muscle regeneration therapies for the elderly.

Posted in Natural aging, the study demonstrates that circulating shuttles called extracellular vesicles, or EVs, deliver genetic instructions for the longevity protein known as Klotho to muscle cells. Loss of muscle function and impaired muscle repair in older mice can be caused by older electric vehicles, which contain fewer copies of these instructions than those in younger animals.

The results are an important step forward in understanding why the ability of muscles to regenerate declines with age.

“We are really excited about this research for several reasons,” said senior author Fabrisia Ambrosio, Ph.D., director of rehabilitation for UPMC International and associate professor of physical medicine and rehabilitation at Pitt. “In a way, it helps us understand the basic biology of how muscle regeneration works and how it doesn’t work with age. Then, taking that information to the next step, we can consider doing use extracellular vesicles as a therapy to counter these ages. -related defects. “

The new study builds on decades of research showing that when old mice receive blood from young mice, youthful characteristics are restored in many cells and tissues. But until now, it was not clear which components of young blood confer these rejuvenating effects.

“We wondered if extracellular vesicles might contribute to muscle regeneration, as these messengers travel between cells via blood and other bodily fluids,” said senior author Amrita Sahu, Ph.D., postdoctoral fellow at Pitt’s Department of Physical Medicine and Rehabilitation. . “Like a message in a bottle, electric vehicles deliver information to target cells.”

Ambrosio and his team collected serum, the fraction of blood that remains after removing blood cells and clotting factors, from young mice and injected it into elderly mice with muscle damage. The mice that received the young serum showed improved muscle regeneration and functional recovery compared to those that received the placebo treatment, but the restorative properties of the serum were lost when the EVs were removed, indicating that these vesicles mediate the beneficial effects of young blood.

Going deeper, the researchers found that electric vehicles pass genetic instructions, or mRNAs, encoding the antiaging protein Klotho to muscle progenitor cells, a type of stem cell that is important for the regeneration of skeletal muscle. Electric vehicles collected from old mice carried fewer copies of the instructions for Klotho than those from young mice, prompting muscle progenitor cells to produce less of this protein.

With age, muscle does not heal as well after damage because scar tissue is deposited instead of restoring the original muscle structure. In previous work, Ambrosio and his team have shown that Klotho is an important regulator of the regenerative capacity of muscle progenitor cells and this protein decreases with age.

New study shows for the first time that age-related changes in EV cargo contribute to Klotho depletion in aged stem cells, suggesting EVs could be developed into new healing therapies damaged muscle tissue.

“Electric vehicles may be beneficial in boosting the capacity for muscle regeneration in the elderly and improving functional recovery after injury,” said Ambrosio, who is also a fellow of the Pitt’s McGowan Institute for Regenerative Medicine. “One of the ideas that we are really passionate about is to design electric vehicles with specific cargoes, so that we can dictate the responses of the target cells.”

Beyond muscles, electric vehicles could also help reverse other effects of aging. Previous work has shown that young blood can improve cognitive performance in older mice. Ambrosio and co-author Radosveta Koldamova, MD, Ph.D., professor of environmental and occupational health at the Graduate School of Public Health in Pitt, won a grant to explore the potential of electric vehicles to reverse cognitive declines associated with age.

The other researchers in the study were Zachary J. Clemens, Sunita N. Shinde, Sruthi Sivakumar, Abish Pius, Bennett Van Houten, Ph.D., Mita Lovalekar, Ph.D., Nicholas F. Fitz, Ph.D. , Iliya Lefterov, MD, Ph.D., and Aaron Barchowsky, Ph.D., all from Pitt; Ankit Bhatia of Carnegie Mellon University; and Silvia Picciolini, Ph.D., Cristiano Carlomagno, Ph.D., Alice Gualerzi, Ph.D., and Marzia Bedoni, Ph.D., all from IRCCS Fondazione Don Carlo Gnocchi.

This research was supported by the National Institutes of Health (NIA R01AG052978, NIA R01AG061005, NIA R01AG066198-01, R33 ES025606-05 and NIH 1S10OD01942-01) and UPMC Enterprises.

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