Methionine adenosyltransferase2A inhibition restores metabolism to improve regenerative capacity and strength of aged skeletal muscle

Nika Rajabian, Izuagie Ikhapoh, Shahryar Shahini, Debanik Choudhury, Ramkumar Thiyagarajan, Aref Shahini, Joseph Kulczyk, Kendall Breed, Shilpashree Saha, Mohamed Alaa Mohamed, Susan B. Udin, Aimee Stablewski, Kenneth Seldeen, Bruce R. Troen, Kirkwood Personius and Stelios T. Andreadis ()
Additional contact information
Nika Rajabian: University at Buffalo, The State University of New York
Izuagie Ikhapoh: University at Buffalo, The State University of New York
Shahryar Shahini: University at Buffalo, The State University of New York
Debanik Choudhury: University at Buffalo, The State University of New York
Ramkumar Thiyagarajan: University at Buffalo and Research Service, Veterans Affairs Western New York Healthcare System
Aref Shahini: University at Buffalo, The State University of New York
Joseph Kulczyk: University at Buffalo, The State University of New York
Kendall Breed: University at Buffalo, The State University of New York
Shilpashree Saha: University at Buffalo
Mohamed Alaa Mohamed: University at Buffalo, The State University of New York
Susan B. Udin: University at Buffalo
Aimee Stablewski: Roswell Park Comprehensive Cancer Institute
Kenneth Seldeen: University at Buffalo and Research Service, Veterans Affairs Western New York Healthcare System
Bruce R. Troen: University at Buffalo and Research Service, Veterans Affairs Western New York Healthcare System
Kirkwood Personius: University at Buffalo
Stelios T. Andreadis: University at Buffalo, The State University of New York

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract We investigate the age-related metabolic changes that occur in aged and rejuvenated myoblasts using in vitro and in vivo models of aging. Metabolic and signaling experiments reveal that human senescent myoblasts and myoblasts from a mouse model of premature aging suffer from impaired glycolysis, insulin resistance, and generate Adenosine triphosphate by catabolizing methionine via a methionine adenosyl-transferase 2A-dependant mechanism, producing significant levels of ammonium that may further contribute to cellular senescence. Expression of the pluripotency factor NANOG downregulates methionine adenosyltransferase 2 A, decreases ammonium, restores insulin sensitivity, increases glucose uptake, and enhances muscle regeneration post-injury. Similarly, selective inhibition of methionine adenosyltransferase 2 A activates Akt2 signaling, repairs pyruvate kinase, restores glycolysis, and enhances regeneration, which leads to significant enhancement of muscle strength in a mouse model of premature aging. Collectively, our investigation indicates that inhibiting methionine metabolism may restore age-associated impairments with significant gain in muscle function.

Date: 2023
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DOI: 10.1038/s41467-023-36483-3

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