Human skeletal muscle macrophages increase following cycle training and are associated with adaptations that may facilitate growth

R Grace Walton,Charlotte A Peterson,Jyothi Mula,Christopher S Fry,Philip A Kern,Beibei Zhu,Jason S Groshong,Bailey D Peck,Brian S Finlin,Kate Kosmac

doi:10.1038/s41598-018-37187-1

Abstract

Skeletal muscle macrophages participate in repair and regeneration following injury. However, their role in physiological adaptations to exercise is unexplored. We determined whether endurance exercise training (EET) alters macrophage content and characteristics in response to resistance exercise (RE), and whether macrophages are associated with other exercise adaptations. Subjects provided vastus lateralis biopsies before and after one bout of RE, after 12 weeks of EET (cycling), and after a final bout of RE. M2 macrophages (CD11b+/CD206+) did not increase with RE, but increased in response to EET (P < 0.01). Increases in M2 macrophages were positively correlated with fiber hypertrophy (r = 0.49) and satellite cells (r = 0.47). M2c macrophages (CD206+/CD163+) also increased following EET (P < 0.001), and were associated with fiber hypertrophy (r = 0.64). Gene expression was quantified using NanoString. Following EET, the change in M2 macrophages was positively associated with changes in HGF, IGF1, and extracellular matrix genes. EET decreased expression of IL6 (P < 0.05), C/EBPβ (P < 0.01), and MuRF (P < 0.05), and increased expression of IL-4 (P < 0.01), TNFα (P < 0.01) and the TWEAK receptor FN14 (P < 0.05). The change in FN14 gene expression was inversely associated with changes in C/EBPβ (r = −0.58) and MuRF (r = −0.46) following EET. In cultured human myotubes, siRNA inhibition of FN14 increased expression of C/EBPβ (P < 0.05) and MuRF (P < 0.05). Our data suggest that macrophages contribute to the muscle response to EET, potentially including modulation of TWEAK-FN14 signaling.

Highlights

Both endurance and resistance exercise promote maintenance of muscle mass and function[1,2]
Using a small subset (N = 7) of this study cohort, we have previously reported that satellite cell and transcriptional responses to resistance exercise (RE) were modulated by EET37
All four biopsies were available for macrophage immunohistochemistry (IHC) from 14 subjects, with baseline and post-exercise training (EET) biopsies available for 23 of the 26 subjects who completed the trial

Summary

Introduction

Both endurance and resistance exercise promote maintenance of muscle mass and function[1,2]. Macrophages participate in muscle repair and regeneration by modulating inflammation, stem cells, cytokines, growth factors, and extracellular matrix. Their role in the physiological adaptation to exercise is relatively unexplored. M1 macrophages produce inflammatory cytokines (TNFα, IL1β) that signal through canonical NFκB and other pathways to promote SC proliferation[7,8]. In later stages of repair, macrophages shift toward M2 activation, and produce anti-inflammatory cytokines (TGFβ, IL10)[9,10], driving non-canonical NFκB signaling[11] and promoting MPC differentiation. Macrophage-derived inflammatory cytokines, including IL1β, TNFα, and TWEAK, are observed in various disease states, and drive muscle atrophy via canonical NFκB signaling. EET caused decreased muscle macrophage content in mice[30], and did not affect muscle macrophage content in rats[31]

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Results

Conclusion