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Skewed macrophage polarization in aging skeletal muscle

ABSTRACT: Skeletal muscle aging is a major causative factor for disability and frailty in the elderly. Recent theories about the origins of the progressive impairment of skeletal muscle with aging emphasize a disequilibrium between damage and repair. Macrophages participate in muscle tissue repair first as pro-inflammatory M1 subtype and then as M2 anti-inflammatory subtype. However, information on macrophage presence in skeletal muscle is still sporadic and the effect of aging on different phenotypes remains unknown. In this study, we sought to characterize the polarization status of macrophages human skeletal muscle at different ages. We found that most macrophages in human skeletal muscle are M2, and that this number increased with advancing age. On the contrary, M1 macrophages decline with aging, making the total number of macrophages invariant with older age. Notably, M2 macrophages co-localized with increasing intermuscular adipose tissue (IMAT) in aging skeletal muscle. The mouse strain BALB/c, intrinsically M2-prone, showed increased IMAT and regenerating myofibers in skeletal muscle, accompanied by elevated expression of adipocyte markers and M2 cytokines. Collectively, we report that polarization of macrophages to the major M2 subtype is associated with IMAT, and propose that increased M2 in aged skeletal muscle may reflect active repair of aging-associated muscle damage.

ORGANISM(S): Mus musculus

PROVIDER: GSE125481 | GEO | 2022/01/01

REPOSITORIES: GEO

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Project description:Inflammation is the natural defensive response of the immune system to an injury or infection and is regulated by small molecule mediators triggering different phases of the inflammatory process. In particular, lipid mediators (LM) and cytokines exhibit crucial regulatory functions in the progression and resolution of inflammation. Macrophages play a central role in this process and can adopt distinct phenotypes with specialized functions depending on their microenvironment: inflammatory M1 macrophages drive inflammation by the release of pro-inflammatory cytokines and LMs, like prostaglandins (PG) and leukotrienes (LT), while resolving M2 macrophages promote inflammation resolution and tissue regeneration by production of anti-inflammatory cytokines and specialized pro resolving mediators (SPM). Aging is associated with chronic and unresolved, low-grade inflammation (“inflammaging”) and aging-related dysfunction of macrophages in the resolution of inflammation and tissue maintenance has been reported. Yet, the underlying molecular mechanisms and functional consequences of latter processes remain poorly understood. Here, we show that polarization of peritoneal macrophages (PM) from geriatric mice towards an M2-like phenotype is impaired versus adult mice, resulting in aberrant LM formation and cytokine release. In PMs isolated from adult mice (PM-A) we observed a shift in LM formation from PGs and LTs to SPMs already after 4 h of polarization towards M2 with interleukin (IL) 4. In contrast, PMs from geriatric mice (PM-G) produced mainly LTs and PGs upon polarization. This pattern persists over the course of 48 h of polarization. Proteomic profiling revealed that polarization of PM A towards M2 yields a more distinct phenotype, clearly separated from M1, when compared to PM-G. We observed similar aging-related changes in the lipidome and cytokine profile of spleen, lung and liver tissue from mice. Hence, we hypothesize that during aging macrophage polarization towards M2 is impaired, which in turn drives chronic inflammation and disturbs tissue maintenance. By combining state-of-the art lipidomic and proteomic profiling we aim to uncover new molecular targets for pharmaceutical interventions to improve therapeutic strategies for elderly patients with chronic inflammatory diseases.

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Skewed macrophage polarization in aging skeletal muscle

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