As we age, our muscles gradually become smaller and weaker and our ability to heal after injury becomes less. In a new study, researchers from UPMC and the University of Pittsburgh identified an important medium for muscle rejuvenation in mice, a finding that could drive muscle regeneration therapies in older adults.
The study, published December 6, 2021 in Nature Aging, demonstrates that cyclic shuttles called extracellular vesicles (EVs) transmit genetic instructions for a longevity protein known as Klotho to muscle cells. Older mice's loss of muscle function and impaired muscle repair may have been driven by aging EVs, which carried fewer copies of these instructions than younger animals.
These findings are an important advance in understanding why muscle regenerative capacity decreases with age.
Dr Fabrisia Ambrosio, senior author of the study, said: "We are very excited about this study, and there are several reasons for this. On the one hand, it helps us understand the basic biology of muscle regeneration and how it fails as we age. Then, taking this information to the next step, we can consider using extracellular vesicles as a therapeutic means to combat these age-related defects. Ambrosio is Director of Rehabilitation at UPMC International and Associate Professor of Physical Medicine and Rehabilitation at the University of Pitt.
The new study builds on decades of research. The study showed that when older mice were given blood from younger mice, many cells and tissues regained their youthful characteristics. But until now, it wasn't clear which components in young blood would bring these rejuvenating effects.
"We wanted to know if extracellular vesicles contribute to muscle regeneration, as these vectors travel between cells through blood and other body fluids, just like information in a bottle, and EVs deliver information to target cells," said Amrita Sahu, lead author of the paper and a postdoctoral fellow in the Department of Physical Medicine and Rehabilitation at the University of Pitt.
Ambrosio and his team collected serum from young mice, the remaining blood portion after removing blood cells and clotting factors, and injected them into older mice with injured muscles. Mice that received the young serum showed stronger muscle regeneration and functional recovery compared to the placebo-treated mice, but when the EV was removed, the serum's recovery properties disappeared, suggesting that these vesicles mediated beneficial effects in young blood.
After further research, the researchers found that EVs transmit genetic instructions, or mRNA, that encode the anti-aging protein Klotho, to muscle progenitor cells, a type of stem cell that is important for skeletal muscle regeneration. EVs collected from older mice carried fewer copies of Klotho instructions than younger mice, which left muscle progenitor cells producing less of this protein.
As we age, muscles do not heal well after damage because scar tissue is deposited rather than restoring the original muscle structure. In earlier work, Ambrosio and her team noted that Klotho is an important regulator of the regenerative capacity of muscle progenitor cells, a protein that decreases with age.
The new study shows for the first time that a shift in age-related EV cargo has led to the depletion of Klotho in older stem cells, suggesting that EVs can be developed into new therapies to heal damaged muscle tissue.
Ambrosio said: "EVs may be beneficial in improving the regenerative capacity of muscles in older adults and improving functional recovery after injury. One idea we're really excited about is to design EVs with specific cargoes so that we can decide on the response of the target cells. ”
In addition to muscle, EVs can also help reverse other effects of aging. Previous work has shown that young blood can improve cognitive abilities in older mice. Ambrosio and his collaborators received a grant to explore the potential of EVs to reverse age-related cognitive decline.