title: Matrix metalloproteinase-9 inhibition improves proliferation and engraftment of myogenic cells in dystrophic muscle of mdx mice.
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.
authors: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, United States of America.
authors: Sajedah M
authors: SM
authors: Hindi
authors: Jonghyun
authors: J
authors: Shin
authors: Yuji
authors: Y
authors: Ogura
authors: Hong
authors: H
authors: Li
authors: Ashok
authors: A
authors: Kumar
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D006085:Graft Survival; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D032446:Myoblasts / Q000187:drug effects / Q000201:enzymology / Q000637:transplantation*; D010641:Phenotype; D061251:Primary Cell Culture; D051880:Receptors, Notch / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D051880:Receptors, Notch; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
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