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Disrupted Macrophage Metabolic Reprogramming in Aged Soleus Muscle During Early Recovery following Disuse Atrophy

ABSTRACT: Aged skeletal muscle is characterized by impaired muscle recovery following disuse and coincides with an impaired muscle pro-inflammatory macrophage response. Macrophage inflammatory status (polarization) is regulated by its metabolic state, but to date, little is understood of macrophage metabolism and its relation to macrophage polarization in the context of muscle recovery and aging. Therefore, the purpose of this study was to thoroughly characterize macrophage metabolism and polarization in aged muscle during early recovery from disuse atrophy using single cell RNA sequencing and functional assays. Young (4-5 mo) and old (20-22 mo) male C57BL/6 mice underwent 14 days of hindlimb unloading followed by 4 days of ambulatory recovery. CD45+ cells were isolated from solei muscles and analyzed using 10x Genomics single cell RNA sequencing. We found that aged M1 macrophage clusters were characterized with an impaired inflammatory and glycolytic transcriptome and this impairment was accompanied by a suppression of HIF-1α and its immediate downstream target GLUT1.

ORGANISM(S): Mus musculus

PROVIDER: GSE158987 | GEO | 2021/08/12

REPOSITORIES: GEO

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Project description:Skeletal muscle atrophy is dictated by the balance between protein synthesis and protein breakdown, known as proteostasis. With advanced age, muscle atrophy contributes to development of co-morbidities, loss of strength and independence, and all-cause mortality. Aging also coincides with the accumulation of senescent cells within skeletal muscle that produce inflammatory products, known as the senescence associated secretory phenotype. Previously, we found that a metformin + leucine (MET+LEU) combination treatment had synergistic effects in aged mice to improve skeletal muscle structure and function during disuse atrophy. Therefore, the objective of this study 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 serum-deprivation (SD) atrophy. Single myofibers were isolated from aged (22-23 mo) C57Bl6/J mice, and human primary myoblasts were extracted from a healthy older adult donor. 25 + 125 µM MET+LEU treatment increased differentiation of myotubes and prevented SD induced atrophy. Low concentration (0.1 + 0.5 µM) MET+LEU had unique effects to prevent myotube atrophy and cause transcriptional reprogramming compared to individual therapies. SD increased inflammatory and cellular senescence pathways that was reversed with MET+LEU treatment. SD resulted in dysregulated proteostasis that was rescued with MET+LEU, and proteasome inhibition with MG-132 also rescued myotube atrophy. Cellular senescence transcriptional pathways and markers increased by SD were reversed with MET+LEU treatment, and dasatinib + quercetin (D+Q) senolytic treatment prevented myotube atrophy similar to MET+LEU. In aged myofibers, MET+LEU prevented SD atrophy, and in human primary myotubes MET+LEU prevented reductions in myonuclei fusion. These data provide evidence that MET+LEU has muscle cell intrinsic properties to prevent atrophy by reversing senescence and improving proteostasis

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Disrupted Macrophage Metabolic Reprogramming in Aged Soleus Muscle During Early Recovery following Disuse Atrophy

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