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

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  • 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
    University at Buffalo
    Center of Excellence in Bioinformatics and Life Sciences
    University at Buffalo)

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.

Suggested Citation

  • Nika Rajabian & Izuagie Ikhapoh & Shahryar Shahini & Debanik Choudhury & Ramkumar Thiyagarajan & Aref Shahini & Joseph Kulczyk & Kendall Breed & Shilpashree Saha & Mohamed Alaa Mohamed & Susan B. Udin, 2023. "Methionine adenosyltransferase2A inhibition restores metabolism to improve regenerative capacity and strength of aged skeletal muscle," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36483-3
    DOI: 10.1038/s41467-023-36483-3
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    References listed on IDEAS

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    1. Daniela Piazzolla & Adelaida R. Palla & Cristina Pantoja & Marta Cañamero & Ignacio Perez de Castro & Sagrario Ortega & Gonzalo Gómez-López & Orlando Dominguez & Diego Megías & Giovanna Roncador & Jos, 2014. "Lineage-restricted function of the pluripotency factor NANOG in stratified epithelia," Nature Communications, Nature, vol. 5(1), pages 1-14, September.
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