TRANSCRIPTOMIC AND CELLULAR RESPONSE TO MECHANICAL OVERLOAD AND THE UNDERLYING ROLE OF MACROPHAGES IN EXTRACELLULAR MATRIX REMODELING

The extracellular matrix (ECM) in skeletal muscle plays an integral role in tissue development, structural support, and force transmission. Upon mechanical loading, including resistance exercise, which alter muscle fiber contractile activity, size, orientation and connectivity, remodeling processes must occur that involve both ECM deposition and degradation. ECM remodeling involves many cell types in muscle, but the focus of our research was directed towards macrophages, which participate in the early immune response to damage and loading. We have consistently demonstrated a significant increase in skeletal muscle macrophage abundance using pan macrophage markers (CD11b/CD68) and anti-inflammatory markers (CD206/CD163) following exercise training in both middle aged and older adults. We report that with 14-weeks of progressive resistance exercise training (PRT) in older adults (>65 years of age), genes involved in ECM remodeling, including MMP14, a master regulator of ECM turnover, were the most upregulated, differentially expressed genes among those identified by RNA-sequencing in muscle biopsies. Following an acute bout of resistance exercise in humans and mechanical overload in mouse, single cell RNA-sequencing indicated that muscle macrophages accumulate MMP14 mRNA. In vitro, we identified leukemia inhibitory factor (LIF), secreted by electrically-stimulate primary human myotubes, as a contributor to upregulation of MMP14 expression in macrophages. The data presented identify a novel mechanism by which skeletal muscle and macrophages interact to promote ECM remodeling in response to mechanical overload.
© 2020 Bailey D. Peck