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: Sajedah M Hindi, Jonghyun Shin, Yuji Ogura, Hong Li, Ashok Kumar
• Journal: PloS one (PLoS One) Vol. 8 Issue 8 Pg. e72121 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23977226 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Matrix Metalloproteinase Inhibitors
• Receptors, Notch
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Animals
• Cell Proliferation
• Cells, Cultured
• Graft Survival
• Macrophages (drug effects, enzymology)
• Matrix Metalloproteinase 9 (metabolism)
• Matrix Metalloproteinase Inhibitors (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred mdx
• Mice, Knockout
• Muscle, Skeletal (metabolism, pathology)
• Muscular Dystrophy, Duchenne (enzymology, pathology, therapy)
• Myoblasts (drug effects, enzymology, transplantation)
• Phenotype
• Primary Cell Culture
• Receptors, Notch (metabolism)
• Wnt Signaling Pathway