Year of Publication

2020

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Health Sciences

Department

Rehabilitation Sciences

First Advisor

Dr. Charlotte A. Peterson

Second Advisor

Dr. Esther E. Dupont-Versteegden

Abstract

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.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2020.514

Funding Information

This study was funded by the National Institute of Aging (R01AG046920) from 2016-2019.

Supplementary Files.zip (3227 kB)
Supplementary Tables

Available for download on Thursday, December 16, 2021

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