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Aging is accompanied by reduced remodeling of skeletal muscle extracellular matrix (ECM), which is exacerbated during recovery following periods of disuse atrophy. Mechanotherapy has been shown to promote ECM remodeling through immunomodulation in adult muscle recovery, but not during the aged recovery from disuse. In order to determine if mechanotherapy promotes ECM remodeling in aged muscle, we performed single cell RNA sequencing (scRNA-seq) of all mononucleated cells in adult and aged rat gastrocnemius muscle recovering from disuse, with (REM) and without mechanotherapy (RE). We show that fibroadipogenic progenitor cells (FAPs) in aged RE muscle are highly enriched in chemotaxis genes (Csf1), but absent in ECM remodeling genes compared to adult RE muscle (Col1a1). Receptor-ligand (RL) network analysis of all mononucleated cell populations in aged RE muscle identified chemotaxis-enriched gene expression in numerous stromal cell populations (FAPs, endothelial cells, pericytes), despite reduced enrichment of genes related to phagocytic activity in myeloid cell populations (macrophages, monocytes, antigen presenting cells). Following mechanotherapy, aged REM mononuclear cell gene expression resembled adult RE muscle as evidenced by RL network analyses and KEGG pathway activity scoring. To validate our transcriptional findings, ECM turnover was measured in an independent cohort of animals using in vivo isotope tracing of intramuscular collagen and histological scoring of the ECM, which confirmed mechanotherapy-mediated ECM remodeling in aged RE muscle. Our results highlight age-related cellular mechanisms underpinning the impairment to complete recovery from disuse, and also promote mechanotherapy as an intervention to enhance ECM turnover in aged muscle recovering from disuse. [ABSTRACT FROM AUTHOR]

It is postulated that testosterone-induced skeletal muscle hypertrophy is driven by myonuclear accretion as the result of satellite cell fusion. To directly test this hypothesis, we utilized the Pax7-DTA mouse model to deplete satellite cells in skeletal muscle followed by testosterone administration. Pax7-DTA mice (6 mo of age) were treated for 5 days with either vehicle [satellite cell replete (SC+)] or tamoxifen [satellite cell depleted (SC-)]. Following a washout period, a testosterone propionate or sham pellet was implanted for 21 days. Testosterone administration caused a significant increase in muscle fiber crosssectional area in SC+ and SC- mice in both oxidative (soleus) and glycolytic (plantaris and extensor digitorum longus) muscles. In SC+ mice treated with testosterone, there was a significant increase in both satellite cell abundance and myonuclei that was completely absent in testosterone-treated SC- mice. These findings provide direct evidence that testosterone-induced muscle fiber hypertrophy does not require an increase in satellite cell abundance or myonuclear accretion. Listen to a podcast about this Rapid Report with senior author E. E. Dupont-Versteegden (https://ajpcell.podbean.com/e/podcast-on-paperthat- shows-testosterone-induced-skeletal-muscle-hypertrophydoes- not-need-muscle-stem-cells/). [ABSTRACT FROM AUTHOR]