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.

Notch signaling genes

“…As described above, our epigenetic findings suggest that Notch signaling plays a role in the myofibers of muscle tissue (Fig. 2) as well as the known role in muscle progenitor cells and satellite cells 3 - 6 . Although we did not analyze satellite cells, which are difficult to obtain from human tissue, previous studies indicate the importance of Notch signaling for muscle satellite cell maintenance, repopulation, differentiation, and niche localization 9 , 12 , 20 , 43 , 53 .…”

Doxycycline Inhibits IL-17-Stimulated MMP-9 Expression by Downregulating ERK1/2 Activation: Implications in Myogenic Differentiation

“…Besides revealing that MMP-9 inhibition augments the proliferation of satellite cells and changes the immune cell milieu as well as expression of significant ligands, receptors, and signaling pathways, this group showed that inhibition of MMP-9 dramatically improves the engraftment of transplanted myoblasts in skeletal muscle of mdx mice (a mouse model of DMD) [42]. Together with our results, this finding adds value to the importance of MMP-9 in muscle regeneration and suggests this enzyme as a possible target in muscle regeneration and repair.…”

Degenerative and regenerative features of myofibers differ among skeletal muscles in a murine model of muscular dystrophy

“…Different muscles have been analyzed in mdx mice after exercise (Weller et al 1990;Brussee et al 1997;Granchelli et al 2000;De Luca et al 2005), administration of drugs (Hodgetts et al 2006), engraftment of somatic cells (Hindi et al 2013;Boldrin et al 2015), and gene modification (Li et al 2009;Heydemann et al 2012). The results obtained and the skeletal muscles analyzed are different in these previous reports.…”