Macrophage metabolic rewiring rejuvenates muscle Raman signatures and cellular remodeling during regrowth in aged mice

Impaired muscle regrowth in aging is underpinned by reduced proinflammatory macrophage function and subsequently impaired muscle cellular remodeling. Macrophage phenotype is metabolically controlled through TCA intermediate accumulation and activation of HIF1A. We hypothesized that transient hypoxia following disuse in old mice would enhance macrophage metabolic inflammatory function, thereby improving muscle cellular remodeling and recovery. Old (20 months) and young adult mice (4 months) were exposed to acute (24 hour) normobaric hypoxia immediately following 14 days of hind limb unloading and assessed during early reambulation (4 and 7 days) compared to age-matched controls. Treated aged mice had improved proinflammatory macrophage profiles, muscle cellular remodeling, and functional muscle recovery to the levels of young control mice. Likewise, young adult mice had enhanced muscle remodeling and functional recovery when treated with acute hypoxia. Treatment in aged mice restored the muscle molecular fingerprint and biochemical spectral patterns (Raman spectroscopy) observed in young mice and strongly correlated with improved collagen remodeling. Finally, intramuscular delivery of hypoxia-treated macrophages recapitulated the muscle remodeling and recovery effects of whole-body hypoxic exposure in old mice. These results emphasize the role of proinflammatory macrophages during muscle regrowth in aging and highlight immunometabolic approaches as a route to improve muscle cellular dynamics and regrowth.