Skewed macrophage polarization in aging skeletal muscle.

Chang‐Yi Cui,Riley K Driscoll,Yulan Piao,Luigi Ferrucci,Chee W Chia,Myriam Gorospe

doi:10.1111/acel.13032

Chang‐Yi Cui, Riley K Driscoll + Show 4 more

Open Access

https://doi.org/10.1111/acel.13032

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Abstract

Skeletal muscle aging is a major cause of disability and frailty in the elderly. The progressive impairment of skeletal muscle function with aging was recently linked to a disequilibrium between damage and repair. Macrophages participate in muscle tissue repair, first as pro‐inflammatory M1 subtype and then as anti‐inflammatory M2 subtype. However, information on the presence of macrophages in skeletal muscle is still sporadic and the effect of aging on macrophage phenotype remains unknown. In this study, we sought to characterize the polarization status of macrophages in skeletal muscle of persons across a wide range of 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 declined with aging, making the total number of macrophages invariant with older age. Notably, M2 macrophages colocalized with increasing intermuscular adipose tissue (IMAT) in aging skeletal muscle. Similarly, aged BALB/c mice showed increased IMAT and M2 macrophages in skeletal muscle, accompanied by slightly increased collagen protein production. 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 impact upon muscle metabolism associated with aging.

Highlights

Skeletal muscle (SKM) is the largest tissue in mammals (Janssen, 2006)
Our findings indicate a connection between macrophages and CD68+/CD206+ (M2) polar‐ ization and intermuscular adipose tissue (IMAT) and suggest that the rise in M2 macrophages may be an adaptive response to repair aged SKM
Macrophages were found to be capable of polarizing into M1 and M2 subtypes, in turn triggering two distinct programs, pro‐inflammatory and anti‐inflammatory, re‐ spectively, that play sequential roles in the repair of tissues including SKM (Mills, 2015)

Summary

| INTRODUCTION

Skeletal muscle (SKM) is the largest tissue in mammals (Janssen, 2006). Skeletal muscle comprises muscle fibers, vasculature, con‐ nective and adipose tissue, and neuromuscular junctions. We further show slightly increased collagen protein deposits in aged mouse SKM, collagen mRNA levels were significantly decreased. 2.1 | M2 macrophages are the most abundant subset in human SKM and their frequency increases with age. We investigated systematically the polarization of macrophages in human aging SKM by collecting muscle (vastus lateralis) biopsies from healthy young (Y), middle‐aged (M), and old (O) participants (Table 1, and see Experimental Procedures). 2.3 | In aging human SKM, M2 macrophages colocalize with IMAT, but not with satellite cells. Immunostaining with specific antibodies showed comparable abundance of collagen pro‐ teins in O and Y SKM sections (Figure 6b). Western blot analyses using an antibody that recognized collagen III revealed slightly increased collagen levels in O SKM (Figure 6d). These data revealed that while collagen mRNA levels were signifi‐ cantly reduced, collagen protein abundance was normal or even slightly increased in O SKM

| DISCUSSION

Findings

| EXPERIMENTAL PROCEDURES