Matrix metalloproteinase-9 inhibition ameliorates pathogenesis and improves skeletal muscle regeneration in muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a fatal X-linked genetic disorder of skeletal muscle caused by mutation in dystrophin gene. Although the degradation of skeletal muscle extracellular matrix, inflammation and fibrosis are the common pathological features in DMD, the underlying mechanisms remain poorly understood. In this study, we have investigated the role and the mechanisms by which increased levels of matrix metalloproteinase-9 (MMP-9) protein causes myopathy in dystrophin-deficient mdx mice. The levels of MMP-9 but not tissue inhibitor of MMPs were drastically increased in skeletal muscle of mdx mice. Besides skeletal muscle, infiltrating macrophages were found to contribute significantly to the elevated levels of MMP-9 in dystrophic muscle. In vivo administration of a nuclear factor-kappa B inhibitory peptide, NBD, blocked the expression of MMP-9 in dystrophic muscle of mdx mice. Deletion of Mmp9 gene in mdx mice improved skeletal muscle structure and functions and reduced muscle injury, inflammation and fiber necrosis. Inhibition of MMP-9 increased the levels of cytoskeletal protein beta-dystroglycan and neural nitric oxide synthase and reduced the amounts of caveolin-3 and transforming growth factor-beta in myofibers of mdx mice. Genetic ablation of MMP-9 significantly augmented the skeletal muscle regeneration in mdx mice. Finally, pharmacological inhibition of MMP-9 activity also ameliorated skeletal muscle pathogenesis and enhanced myofiber regeneration in mdx mice. Collectively, our study suggests that the increased production of MMP-9 exacerbates dystrophinopathy and MMP-9 represents as one of the most promising therapeutic targets for the prevention of disease progression in DMD.

MicroRNA-431 accelerates muscle regeneration and ameliorates muscular dystrophy by targeting Pax7 in mice

“…Although this disease is caused primarily by a mutation in the gene encoding dystrophin 46 , several genes slow disease progression in mdx mice [47][48][49][50] . Thus, therapeutic strategies may not be limited to those directly targeting the dystrophin gene.…”

The role of iNOS in cholesterol-induced liver fibrosis

“…MMPs are a family of zinc-containing enzymes involved in degradation and remodeling of the components of the ECM under both physiological and pathophysiological conditions. 50 Among this family, MMP-9 represents the largest and most complex member. 51 Uncontrolled increases of MMP-9 activity have been implicated in contributing to tissue degradation in many pathological conditions, including scarring, following myocardial injury, central nervous system injury, lung injury, kidney disease, and liver injury.…”

Cathepsin S Contributes to the Pathogenesis of Muscular Dystrophy in Mice

“…Numerous studies have demonstrated that increased activity of select proteases in the skeletal muscle of mouse models of muscular dystrophy, such as the calpains and matrix metalloproteinases, contributes to tissue histopathology (7,14). For example, genetic inhibition of a broad class of serine proteases achieved by overexpressing the inhibitor Serpina3n in skeletal muscle attenuated dystrophic disease in two mouse models of muscular dystrophy (15).…”