Abstract
Duchenne muscular dystrophy (DMD) caused by loss of cytoskeletal protein dystrophin is a devastating disorder of skeletal muscle. Primary deficiency of dystrophin leads to several secondary pathological changes including fiber degeneration and regeneration, extracellular matrix breakdown, inflammation, and fibrosis. Matrix metalloproteinases (MMPs) are a group of extracellular proteases that are involved in tissue remodeling, inflammation, and development of interstitial fibrosis in many disease states. We have recently reported that the inhibition of MMP-9 improves myopathy and augments myofiber regeneration in mdx mice (a mouse model of DMD). However, the mechanisms by which MMP-9 regulates disease progression in mdx mice remain less understood. In this report, we demonstrate that the inhibition of MMP-9 augments the proliferation of satellite cells in dystrophic muscle. MMP-9 inhibition also causes significant reduction in percentage of M1 macrophages with concomitant increase in the proportion of promyogenic M2 macrophages in mdx mice. Moreover, inhibition of MMP-9 increases the expression of Notch ligands and receptors, and Notch target genes in skeletal muscle of mdx mice. Furthermore, our results show that while MMP-9 inhibition augments the expression of components of canonical Wnt signaling, it reduces the expression of genes whose products are involved in activation of non-canonical Wnt signaling in mdx mice. Finally, the inhibition of MMP-9 was found to dramatically improve the engraftment of transplanted myoblasts in skeletal muscle of mdx mice. Collectively, our study suggests that the inhibition of MMP-9 is a promising approach to stimulate myofiber regeneration and improving engraftment of muscle progenitor cells in dystrophic muscle.
Highlights
Duchenne muscular dystrophy (DMD) is caused by null mutations in the dystrophin gene that encodes a membraneassociated structural protein [1,2,3]
These results suggest that inhibition of Matrix metalloproteinases (MMPs)-9 does not affect skeletal muscle structure in mdx mice at the prenecrotic stage
Skeletal muscle has remarkable ability to regenerate in response to injury by activation of undifferentiated myogenic precursor cells [39], a mechanism known to be impaired in DMD patients [44,45,46]
Summary
Duchenne muscular dystrophy (DMD) is caused by null mutations in the dystrophin gene that encodes a membraneassociated structural protein [1,2,3]. Previous studies from our and other groups have shown that the abundance and activity of MMP-9 are increased in skeletal muscle of animal models of DMD [6,7,8,9]. We have previously reported that the inhibition of MMP-9 using genetic or pharmacological approaches considerably improves skeletal muscle structure and function in both young and aged mdx mice [7,11,12,13]. Of note are the findings that there is a marked increase in number of centronucleated and embryonic myosin heavy chain (eMyHC)positive myofibers upon ablation of MMP-9 in adult mdx mice suggesting that inhibition of MMP-9 improves regeneration in dystrophic muscle [13]. The mechanisms by which MMP-9 regulates skeletal muscle regeneration in mdx mice remain unknown
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