Open AccessRegulation of aged skeletal muscle regeneration by circulating extracellular vesicles
Author(s) -
Amrita Sahu,
Zachary Clemens,
Sunita Shinde,
Sruthi Sivakumar,
Abish Pius,
Ankit Bhatia,
Silvia Picciolini,
Cristiano Carlomagno,
Alice Gualerzi,
Marzia Bedoni,
Bennett Van Houten,
Mita Lovalekar,
Nicholas F. Fitz,
Iliya Lefterov,
Aaron Barchowsky,
Radosveta Koldamova,
Fabrisia Ambrosio
Publication year - 2021
Publication title -
nature aging
Language(s) - English
Resource type - Journals
ISSN - 2662-8465
DOI - 10.1038/s43587-021-00143-2
Subject(s) - skeletal muscle , regeneration (biology) , klotho , biology , microbiology and biotechnology , extracellular vesicles , sarcopenia , medicine , endocrinology , phenocopy , kidney , phenotype , biochemistry , gene
Heterochronic blood exchange (HBE) has demonstrated that circulating factors restore youthful features to aged tissues. However, the systemic mediators of those rejuvenating effects remain poorly defined. We show here that the beneficial effect of young blood on aged muscle regeneration was diminished when serum was depleted of extracellular vesicles (EVs). Whereas EVs from young animals rejuvenate aged cell bioenergetics and skeletal muscle regeneration, aging shifts EV subpopulation heterogeneity and compromises downstream benefits on recipient cells. Machine learning classifiers revealed that aging shifts the nucleic acid, but not protein, fingerprint of circulating EVs. Alterations in sub-population heterogeneity were accompanied by declines in transcript levels of the pro-longevity protein, α-Klotho, and injection of EVs improved muscle regeneration in a Klotho mRNA-dependent manner. These studies demonstrate that EVs play a key role in the rejuvenating effects of HBE and that Klotho transcripts within EVs phenocopy the effects of young serum on aged skeletal muscle.