Abstract
The current model for repair of damaged tissue includes immune cells, mediating the progression from a pro-inflammatory to an anti-inflammatory environment. How this process changes with aging in human skeletal muscle under conditions of physiological exercise loading remains unclear. To investigate this, 25 elderly males (mean age 70 ± SD 7 years), as well as 12 young (23 ± 3 years) and 12 elderly (74 ± 3 years) females, performed a unilateral bout of heavy resistance leg extension exercise. Biopsies were collected from the vastus lateralis muscle of the rested (control) leg, and post exercise from the exercised leg at 4.5 h, and on days 1, 4, and 7 for the male participants, or on day 5 for the female participants. Total macrophages (CD68+) as well as pro- (CD11b+) and anti-inflammatory (CD163+, CD206+) subpopulations were identified on sections by immunohistochemistry. Gene expression levels of COL1A1, TNF-a, CD68, myostatin, TCF7L2, IL-1B, IL-1R, IL-10, and Ki67 were determined by real-time RT-PCR. At rest, the muscle tissue from the elderly vs. young females was characterized by higher gene expression levels of CD68, IL-10, lower myostatin mRNA, and trends for a greater number of macrophages, while COL1A1 mRNA post exercise values were greater in the elderly vs young. For the male participants, mRNA levels of the inflammatory cytokines IL-1B, IL-1R were elevated in the early phase following exercise, followed by increases in COL1A1 and Ki67 on days 4 and 7. In general, exercise induced increases in all types of macrophages counted in the elderly, but not in young, individuals. Cells expressing CD68, CD11b, and CD206 simultaneously were the most frequently observed cell type, which raises the possibility that pure pro- and anti-inflammatory macrophages populations do not exist in healthy human skeletal muscle within the spectrum of tissue remodeling induced by physiological exercise designed to induce hypertrophy. Together these data provide insight into the time course of macrophage activity and associated molecular targets in human skeletal muscle in the context of aging and exercise.
Highlights
Skeletal muscle is a plastic tissue with a significant capacity to regenerate and adapt following severe damage, even in elderly individuals in their 60s (Karlsen et al, 2020)
The main findings of this study are gradually increasing numbers of macrophages and their subpopulations in response to a single bout of physiological exercise in the skeletal muscle of healthy elderly males and females, in accordance with changes in gene expression levels of inflammatory and collagen targets during the hours and days post exercise
We report for the first time, that the most commonly observed macrophage cell type was positive for all three markers of the macrophage markers CD68, CD11b, and CD206, suggesting that, within the physiological range of exercise-induced perturbations to healthy skeletal muscle, pure pro- or anti-inflammatory macrophages do not exist
Summary
Skeletal muscle is a plastic tissue with a significant capacity to regenerate and adapt following severe damage, even in elderly individuals in their 60s (Karlsen et al, 2020). The developing model for repair of damaged tissue includes immune cells, mediating the progression from a pro-inflammatory response to an anti-inflammatory state (Arnold et al, 2007; Tidball and Villalta, 2010; Saclier et al, 2013a) This process is precisely regulated and is crucial for proper regeneration, as evidenced in studies perturbing the infiltration sequence to later identify altered and impaired muscle regeneration (Chazaud, 2014). Macrophage phenotypes are generally classified into two opposing categories: (1) pro-inflammatory macrophages (M1) containing phagocytic properties, enhanced microbicidal capacity and a high secretion of pro-inflammatory cytokines (IL-1B and TNF-a), or (2) antiinflammatory macrophages (M2) associated with anti-apoptosis, tissue repair and growth factors (Mosser and Edwards, 2008). Cytokines expressed by macrophages have been shown to regulate myogenic precursor cell fate (Arnold et al, 2007; Saclier et al, 2013a; Chazaud, 2014) further supporting a role for macrophages as key players in muscle regeneration, repair and maintenance
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