Acute Hypoxia Following Disuse Atrophy in Aged Mice Enhances Cellular Remodeling and Whole-body Strength During Early Recovery

Abstract

Age-related impairments in muscle recovery following disuse atrophy are associated with altered macrophage metabolism and blunted inflammatory function. HIF-1α is a key regulator of macrophage metabolism and inflammatory function. Therefore, we investigated the effects of acute hypoxia on muscle recovery following disuse in aging. We hypothesized that transient hypoxic exposure following disuse in aged mice would enhance macrophage metabolism and inflammatory status, resulting in improved muscle cellular remodeling and recovery. Accordingly, old (~20 months) and young adult male mice (~4 months) were exposed to acute (24 hours) normobaric hypoxia (8% O2) immediately following 14-days hindlimb unloading. We characterized muscle phenotype and function during early recovery (4- and 7-days) with and without hypoxia exposure. We found that acute hypoxia stimulated the expression of inflammatory (TNF-α, VEGF p<0.01) and glycolytic transcripts (PFK-1 p<0.05), LDH, PDH p=0.08) downstream of HIF-1α in aged skeletal muscle under basal conditions. Following disuse atrophy, transient hypoxic exposure enhanced macrophage inflammatory function, indicated by increased phagocytosis capacity (p<0.01), and promoted early skeletal muscle cellular remodeling events, including enhanced muscle satellite cell content (p<0.05). Furthermore, these effects facilitated the recovery of whole-body strength in aged mice indicated by a return to baseline values (p>0.05). The results of this investigation suggest that hypoxic exposure following disuse atrophy promoted inflammatory macrophage function, muscle cellular remodeling, and enhanced early recovery in aged mice. These findings elucidate the potential benefits of hypoxia in manipulating macrophage function to ameliorate age-related deficits in muscle recovery following disuse atrophy. This research was supported by R01AG076075 (MJD) and the National Institutes of Health Ruth L. Kirschstein National Research Service Award 5T32DK091317 from the National Institute of Diabetes and Digestive and Kidney Diseases. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.