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1.
Nat Commun ; 14(1): 886, 2023 02 16.
Article in English | MEDLINE | ID: mdl-36797255

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.


Subject(s)
Aging, Premature , Insulin Resistance , Mice , Animals , Humans , Aged , Methionine Adenosyltransferase/genetics , Methionine Adenosyltransferase/metabolism , Methionine/metabolism , Aging, Premature/metabolism , Muscle, Skeletal/metabolism , Signal Transduction , Racemethionine/metabolism
2.
Aging Cell ; 22(3): e13764, 2023 03.
Article in English | MEDLINE | ID: mdl-36625257

ABSTRACT

Cellular senescence leads to the depletion of myogenic progenitors and decreased regenerative capacity. We show that the small molecule 2,6-disubstituted purine, reversine, can improve some well-known hallmarks of cellular aging in senescent myoblast cells. Reversine reactivated autophagy and insulin signaling pathway via upregulation of Adenosine Monophosphate-activated protein kinase (AMPK) and Akt2, restoring insulin sensitivity and glucose uptake in senescent cells. Reversine also restored the loss of connectivity of glycolysis to the TCA cycle, thus restoring dysfunctional mitochondria and the impaired myogenic differentiation potential of senescent myoblasts. Altogether, our data suggest that cellular senescence can be reversed by treatment with a single small molecule without employing genetic reprogramming technologies.


Subject(s)
Autophagy , Cellular Senescence , Morpholines , Muscle Development , Myoblasts, Skeletal , Protein Kinase Inhibitors , Purines , Cellular Senescence/drug effects , Morpholines/pharmacology , Purines/pharmacology , Protein Kinase Inhibitors/pharmacology , Humans , Myoblasts, Skeletal/drug effects , Myoblasts, Skeletal/physiology , Autophagy/drug effects , Insulin/metabolism , AMP-Activated Protein Kinase Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Glycolysis/drug effects , Citric Acid Cycle/drug effects , Insulin Resistance , Cells, Cultured , Muscle Development/drug effects
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