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

## TL;DR

Old mice showed improved muscle recovery after macrophage metabolic changes via hypoxia, matching young mice's performance.

## Contribution

Transient hypoxia rejuvenates aged macrophages, enhancing muscle recovery through metabolic rewiring.

## Key findings

- Hypoxia-treated macrophages improved muscle cellular remodeling in aged mice.
- Muscle Raman signatures in aged mice were restored to young levels after treatment.
- Intramuscular delivery of hypoxia-treated macrophages mimicked whole-body hypoxia effects.

## Abstract

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.

Macrophages are dysfunctional in aging and contribute to impaired muscle recovery. We show that aged macrophage function can be reversed by metabolically altering macrophage function using transient hypoxia thereby restoring muscle recovery to young levels.