Abstract
It remains unclear how exercise, as an entropic event, brings benefit against human aging. Here we examined longitudinal changes of p16Ink4a+ senescent cells in skeletal muscle of young men (aged 22.5±1.7 y) before and after resistance exercise (0 h and 48 h) with multiple biopsies at two different protein availabilities: low protein (14%) and isocaloric high protein (44%) supplemented conditions. Immunohistochemistry analysis of muscle cross-sections using p16Ink4a and CD34 antibodies confirmed that the detected senescent cells were endothelial progenitor cells. Leukocyte infiltration into skeletal muscle increased during resistance exercise. The senescent cells in muscle decreased (-48%, P < 0.01) after exercise for 48 h. Low protein supplementation resulted in greater infiltrations of both CD68+ phagocytic macrophage and leukocyte, further decreased p16Ink4a+ senescent cells (-73%, P < 0.001), and delayed increases in regenerative CD163+ macrophage in skeletal muscle, compared with high protein supplemented condition. Significant gain in muscle mass after 12 weeks of training occurred only under high protein supplemented condition. Conclusion: Rapid senescent cell clearance of human skeletal muscle during resistance exercise seems to associate with enhanced in situ phagocytosis. High protein availability accelerates resolution of muscle inflammation and promotes muscle increment after training.
Highlights
Most of the cells in the human body are continuously aging, dying and regenerating to gradually evolve a fairly stable size of multicellular system with a wide range of cell ages [1]
Co-localization of p16Ink4a+ and CD34+ signals on muscle cross-section at baseline reveals that the detected senescent cells in vastus lateralis muscle of young men were endothelial progenitor cells (Figure 2, upper panel)
A slightly greater decrease in p16Ink4a+ cells was observed with the low protein supplemented condition 48 h after exercise (-73% vs. baseline, P < 0.001) compared with the high protein supplemented condition (Figure 2, lower panel)
Summary
Most of the cells in the human body are continuously aging, dying and regenerating to gradually evolve a fairly stable size of multicellular system with a wide range of cell ages [1]. Skeletal muscle is the largest tissue of the human body, in which cell lifespan varies considerably among different cell types. Selective elimination of senescence cells in skeletal muscle and other tissues has been shown to increase lifespan in mice [3], suggesting a promising approach for anti-aging intervention. The protein p16Ink4a, a cyclin-dependent kinase inhibitor CDKN2A, is a widely used senescence marker expressed in aged cells [4,5,6]. P16Ink4a+ senescence cells in human skeletal muscle are rarely studied. It is currently unclear whether senescent cells are accumulated in human skeletal muscle at young age and whether exercise has significant influence on its number
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