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Cellular senescence and disrupted proteostasis induced by myotube atrophy are prevented with low-dose metformin and leucine cocktail.
Petrocelli, Jonathan J; de Hart, Naomi M M P; Lang, Marisa J; Yee, Elena M; Ferrara, Patrick J; Fix, Dennis K; Chaix, Amandine; Funai, Katsuhiko; Drummond, Micah J.
Afiliación
  • Petrocelli JJ; Department of Physical Therapy and Athletic, University of Utah, Salt Lake City, UT 84112, USA.
  • de Hart NMMP; Department of Physical Therapy and Athletic, University of Utah, Salt Lake City, UT 84112, USA.
  • Lang MJ; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 84112, USA.
  • Yee EM; Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA.
  • Ferrara PJ; Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA.
  • Fix DK; Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA.
  • Chaix A; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 84112, USA.
  • Funai K; Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA.
  • Drummond MJ; Department of Physical Therapy and Athletic, University of Utah, Salt Lake City, UT 84112, USA.
Aging (Albany NY) ; 15(6): 1808-1832, 2023 03 20.
Article en En | MEDLINE | ID: mdl-36947713
ABSTRACT
Aging coincides with the accumulation of senescent cells within skeletal muscle that produce inflammatory products, known as the senescence-associated secretory phenotype, but the relationship of senescent cells to muscle atrophy is unclear. Previously, we found that a metformin + leucine (MET+LEU) treatment had synergistic effects in aged mice to improve skeletal muscle structure and function during disuse atrophy. Therefore, the study's purpose was to determine the mechanisms by which MET+LEU exhibits muscle atrophy protection in vitro and if this occurs through cellular senescence. C2C12 myoblasts differentiated into myotubes were used to determine MET+LEU mechanisms during atrophy. Additionally, aged mouse single myofibers and older human donor primary myoblasts were individually isolated to determine the translational potential of MET+LEU on muscle cells. MET+LEU (25 + 125 µM) treatment increased myotube differentiation and prevented myotube atrophy. Low concentration (0.1 + 0.5 µM) MET+LEU had unique effects to prevent muscle atrophy and increase transcripts related to protein synthesis and decrease transcripts related to protein breakdown. Myotube atrophy resulted in dysregulated proteostasis that was reversed with MET+LEU and individually with proteasome inhibition (MG-132). Inflammatory and cellular senescence transcriptional pathways and respective transcripts were increased following myotube atrophy yet reversed with MET+LEU treatment. Dasatinib + quercetin (D+Q) senolytic prevented myotube atrophy similar to MET+LEU. Finally, MET+LEU prevented loss in myotube size in alternate in vitro models of muscle atrophy as well as in aged myofibers while, in human primary myotubes, MET+LEU prevented reductions in myonuclei fusion. These data support that MET+LEU has skeletal muscle cell-autonomous properties to prevent atrophy by reversing senescence and improving proteostasis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Metformina Límite: Aged / Animals / Humans Idioma: En Revista: Aging (Albany NY) Asunto de la revista: GERIATRIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Metformina Límite: Aged / Animals / Humans Idioma: En Revista: Aging (Albany NY) Asunto de la revista: GERIATRIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
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