Exercise Improves Ability of Extracellular Vesicles to Enhance Aged Skeletal Muscle Regeneration
- Exercise has potent rejuvenating effects, including improved skeletal muscle strength, and increasing evidence points to extracellular vesicles (EVs) as potential mediators of those changes.
- In aged mice, this study examined whether skeletal muscle contraction enhances the therapeutic properties of EVs to restore skeletal muscle healing capacity.
- Ten days of repetitive skeletal muscle contractions generated by neuromuscular electrical stimulation (NMES) drove significant beneficial changes in EV surface marker expression and biomolecular cargoes.
- EVs isolated from the serum of aged animals that completed the NMES protocol improved skeletal muscle contractile force capacity when injected into injured skeletal muscle of sedentary aged mice.
- A better understanding of how NMES boosts the therapeutic effect of aged EVs should enable the development of regenerative rehabilitation-based EV therapeutics for the aging population.
Accumulating evidence suggests exercise slows the age-related loss of skeletal muscle mass, function, and regenerative capacity because it stimulates the release of rejuvenating "myokines" into the circulation. Many of these youthful factors seem to be packaged within extracellular vesicles (EVs) — lipid nanoparticles containing proteins, lipids, and genetic material.
Exercise has beneficial effects on the release of EVs and the composition of their cargoes. Now, researchers at Spaulding Rehabilitation Hospital have first observed in aged animals that these changes result from increased skeletal muscle activity. Fabrisia Ambrosio, PhD, of the Spaulding Discovery Center for Musculoskeletal Recovery, and colleagues report in Experimental Gerontology.
The researchers randomly assigned aged mice to undergo either five sessions of neuromuscular electrical stimulation (NMES), a common modality used in rehabilitation clinics, over 10 days or an equivalent amount of handling and anesthesia. Two days after the final NMES session, EVs from all animals were analyzed and concentrated.
Tibialis anterior muscle injury was induced in other aged mice, and two and four days later, they received intramuscular injections of concentrated EVs from NMES-exposed or control mice. Contractile testing was performed 14 days after injury.
Effects of NMES on EVs
Muscle contractile activity elicited by NMES decreased the density of surface protein CD63 on circulating EVs compared with controls. Previous work has shown expression levels of CD63 increase with age and inversely correlate with pro-myogenic effects on target cells so that NMES may impart a more youthful signature in circulating EVs.
NMES also induced significant changes in EV sugar and lipid composition. Lipids play an important role in EV biogenesis, EV secretion, and delivery of cargoes to target cells, suggesting the changes may affect skeletal muscle metabolic function.
Physiologic Relevance of EV Changes
EVs isolated from the serum of NMES-exposed mice improved contractile muscle recovery when injected into injured aged mice. Intriguingly, the recovery was similar to that seen in a previous study by Dr. Ambrosio and colleagues when EVs from young mice were injected into injured aged skeletal muscle, as reported in Nature Aging.
Potential for Clinical Application
Regenerative rehabilitation is a growing field, and improving skeletal muscle healing capacity is a key target for improving mobility, quality of life, and lifespan. A better understanding of how NMES enhances the therapeutic effect of aged EVs should enable the development of regenerative rehabilitation-based EV therapeutics for the aging population.