|Institution:||University of California – San Diego|
|Keywords:||Cellular biology; duchenne muscular dystrophy; extracellular matrix; mass spectroscopy; rotator cuff tear; skeletal muscle progenitor|
|Full text PDF:||http://www.escholarship.org/uc/item/0bt3p395|
Skeletal muscle progenitor cells (SMPs) are critical for muscle repair in responseto injury. In vivo, SMPs reside in a niche under the basement membranein muscle fibers and will activate and proliferate or differentiate in response tosoluble factors released during injury. Here we sought to use two human muscledisorders, chronic rotator cuff tendon (RCT) tears and Duchenne muscular dystrophy (DMD), to characterize changes to the SMP niche in vivo and corresponding changes in SMP phenotype maintenance ex vivo. Tears in RCTs have known long term effects on RC muscle atrophy, fibrosis, and fatty infiltration, with lasting damage even after surgical tendon repair. The inability of the RC muscles to recover from chronic RC tear indicates possible defects in muscle repair mechanisms. We investigated if muscle injury state was a crucial factor during human SMP expansion and differentiation ex vivo. SMPs were isolated from muscles in patients with no, partial-thickness (PT), or full-thickness (FT) RCT tears. Despite using growth factors, physiological niche stiffness, and muscle-mimetic extracellular matrix (ECM) proteins, we found that SMPs isolated from human RC muscle with RCT tears proliferated slower but fused into myosin heavy chain (MHC)-positive myotubes at higher rates than SMPs from untorn RCTs. Proteomic analysis of RC muscle tissue revealed shifts in muscle composition with pathology, as muscle from massive RCTs had increased ECM deposition compared with no tear RC muscle. Similarly, a proteomic analysis of muscle tissue taken from DMD patients revealed corresponding shifts in ECM and cytoskeletal protein expression with disease. Both analyses illustrate potential changes in the SMP niche, with increased fibrosis and decreases in basement membrane proteins. Together these data underscore the importance of how the niche, both in and ex vivo, prime SMPs for expansion, self-renewal and differentiation.