An altered response in macrophage phenotype following damage in aged human skeletal muscle: implications for skeletal muscle repair

Abstract

The purpose of this study was to test the hypothesis that macrophage polarization is altered in old compared to young skeletal muscle, possibly contributing to the poor satellite cell response observed in older muscle tissue. Muscle biopsies were collected prior to and at 3, 24, and 72 h following a muscle‐damaging exercise in young and old individuals. Immunohistochemistry was used to measure i.m. macrophage content and phenotype, and cell culture experiments tested macrophage behavior and influence on primary myoblasts from older individuals. We found that macrophage infiltration was similar between groups at 24 (young: 3712 ± 2407 vs. old: 5035 ± 2978 cells/mm3) and 72 (young: 4326 ± 2622 vs. old: 5287 ± 2248 cells/mm3) hours postdamage, yet the proportion of macrophages that expressed the proinflammatory marker CD11b were markedly lower in the older subjects (young: 74.5 ± 15 vs. old: 52.6 ± 17%). This finding was coupled with a greater overall proportion of CD206+, anti‐inflammatory macrophages in the old (group: P = 0.0005). We further demonstrate in vitro that proliferation, and in some cases differentiation, of old primary human myoblasts increase as much as 30% when exposed to a young macrophage‐conditioned environment. Collectively, the data suggest that old macrophages appear less capable of adapting and maintaining inflammatory function, which may contribute to poor satellite cell activation and delayed recovery from muscle damage.—Sorensen, J. R., Kaluhiokalani, J. P., Hafen, P. S., Deyhle, M. R., Parcell, A. C., Hyldahl, R. D. An altered response in macrophage phenotype following damage in aged human skeletal muscle: implications for skeletal muscle repair. FASEB J. 33,10353–10368 (2019). http://www.fasebj.org

Macrophage Subpopulations and the Acute Inflammatory Response of Elderly Human Skeletal Muscle to Physiological Resistance Exercise

“…The exercise induced increase seen for CD68+ cells and CD206+ cells in elderly females was expected and aligns with the findings observed among the male participants. Unexpectedly, no changes in macrophage counts were found in the young group, in contrast to other studies detecting increased numbers of pro-inflammatory macrophages in young individuals following a heavy resistance exercise bout (Przybyla et al, 2006;Sorensen et al, 2019). Whether our findings are related to age per se is difficult to determine.…”

“…Building on these studies, and to address the paucity of knowledge on the time course of the macrophage response in young and elderly healthy individuals, the main purpose of this study was to compare the inflammatory profile of young and elderly skeletal muscle at rest and in response to a single bout of physiological resistance exercise. We hypothesized that, when compared to younger individuals, the skeletal muscle of elderly individuals would be characterized by a greater presence of anti-inflammatory macrophages, in accordance with earlier work (Sorensen et al, 2019) reflected by a corresponding gene expression profile. Furthermore, we hypothesized that the macrophage response to exercise would be dominated by anti-inflammatory macrophages in the elderly, but not young, participants.…”

“…Indeed it has been shown that resident anti-inflammatory muscle macrophages are associated with exercise−mediated increases in skeletal muscle fiber size, suggesting a role in muscle growth (Walton et al, 2019a). Additionally a study found that anti-inflammatory macrophages in elderly are more prevalent than in young subjects prior to, and following, a muscle damaging protocol (Sorensen et al, 2019). In support of this, we detected higher levels of IL-10 and CD68 gene expression in the muscle of the control leg in the elderly compared to young females.…”

“…Similarly, in a group of individuals ranging in age from 29 to 68, 12 weeks of endurance cycle training was observed to increase the anti-inflammatory macrophage content of the working muscles, where resident anti-inflammatory muscle macrophages are associated with exercise-mediated increases in skeletal muscle fiber size, suggesting a role in muscle growth (Walton et al, 2019b). Of the few studies comparing young and elderly subjects, recent work has investigated local macrophage content using a muscle damage protocol and found infiltration sequences mimicking the pattern of that seen in animal studies, and also showing differences between young and elderly subjects (Sorensen et al, 2019). This supports the findings from an earlier study where cellular and molecular differences between young and elderly individuals were observed 3 days after a physiological bout of resistance exercise (Przybyla et al, 2006).…”

Muscle Microbiopsy to Delineate Stem Cell Involvement in Young Patients: A Novel Approach for Children With Cerebral Palsy

“…Obviously, many other cells, such as macrophages and fibroblasts could play a role in the CP pathology and their implication should not be neglected. Those cells would be interesting targets for future research (Peterson et al, 2012;Lemos et al, 2015;Deyhle and Hyldahl, 2018;Von Walden et al, 2018;Wang et al, 2019;Sorensen et al, 2019). Similarly, the relevance of other muscle stem cell populations not investigated in the current study needs to be considered in future studies.…”