DISCUSSION
disuse, muscle atrophy, human primary muscle FAPs, fibrosis, disuse atrophy
FAP, MUSCLE ATROPHY, FIBROSIS, EVENTS, DISUSE ATROPHY
In this randomized placebo‐controlled trial, we provided glucose‐tolerant older adults with a clinical dose of metformin during bed rest to capitalize on the senomorphic properties of metformin in order to improve collagen remodeling and cellular senescence during disuse and recovery. The major findings from this study were that metformin‐treated individuals were characterized by higher type I myofiber CSA size after bed rest and less muscle fibrosis during recovery corresponding to reduced markers of senescence/SASP in whole muscle and isolated human primary muscle FAPs. We also observed a positive correlation of whole muscle p21 transcription as well as SA‐β‐galactosidase+ FAP cells with muscle collagen deposition after recovery, suggesting that cellular senescence in whole muscle and FAPs may be related to aberrant collagen remodeling events. Together, pre‐loading with metformin may alleviate excess muscle collagen deposition during recovery from disuse in aging by reducing skeletal muscle and FAP senescence/SASP.A primary finding from this study was that metformin prevented bed rest induced myofiber‐type specific cross‐sectional area loss. Metformin has previously shown preferential effects toward oxidative fibers to prevent slow‐to‐fast switching during disuse atrophy in rats (Sharlo et al., Metformin has been well described to have anti‐inflammatory properties, specifically through inhibition of nuclear factor kappa B (NF‐κB) signaling (Kulkarni et al., In coordination with macrophages, FAPs play an essential role in the proper remodeling of skeletal muscle following injury (Abramowitz et al., In summary, metformin treatment 2 weeks before and during disuse improved older adult myofiber remodeling during early re‐ambulation through alterations in collagen deposition. The effects of metformin on collagen deposition may be related to increased anti‐inflammatory transcriptional programs and reduced whole muscle and muscle resident FAP senescence/SASP. We conclude that short term delivery of metformin may be beneficial to ameliorate muscle atrophy and improve muscle recovery during short‐term recovery following disuse in older adults by targeting muscle cellular senescence/SASP.