The innate immune cells known as macrophages adopt different packages of behaviors (known as polarizations) depending on circumstances. Most research is focused on the difference between the pro-inflammatory M1 polarization and the anti-inflammatory M2 polarization. M2 is considered to be more regenerative, and many issues in aging are thought to involve the presence of too many M1 macrophages. Yet M1 macrophages do play a role in regeneration, as noted here, and this contribution is also disrupted with age to inhibit the ability to regrow muscle in older individuals. This is one of the aspects of macrophage behavior that illustrates the limitations of the simple M1/M2 model; the underlying reality is more of a spectrum of behaviors, and one M1-like macrophage is not necessarily undertaking the same tasks as another.
Impaired muscle regrowth in aging is underpinned by reduced pro-inflammatory macrophage function and subsequently impaired muscle cellular remodeling. The essential role of pro-inflammatory macrophages during tissue remodeling are well appreciated given that they are early responders to facilitate the clearance of tissue debris and initiate intracellular communication such as stimulation of satellite cell proliferation and regulation of the deleterious accumulation of collagen and intramuscular adipose from fibroblasts and fibro-adipogenic progenitors.
Macrophage phenotype is metabolically controlled through citric acid cycle intermediate accumulation and activation of hypoxia-inducible factor 1-alpha (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 (24h) normobaric hypoxia immediately following 14-days of hindlimb unloading and assessed during early re-ambulation (4- and 7-days) compared to age-matched controls.
Treated aged mice had improved pro-inflammatory 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 to 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 pro-inflammatory macrophages during muscle regrowth in aging and highlight immunometabolic approaches as a route to improve muscle cellular dynamics and regrowth.
Link: https://doi.org/10.1172/jci.insight.194303
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