Duchenne muscular dystrophy (DMD), caused by mutations in the
dystrophin gene, involves severe muscle degeneration,
inflammation,
fibrosis, and early death in afflicted boys.
Matrix metalloproteinases (
MMPs) are extracellular
proteases that cause tissue degradation in several disease states. In this study, we tested the hypothesis that the expression levels of various
MMPs are abnormally increased and that their inhibition will ameliorate muscle pathogenesis in animal models of DMD. Our results show that the transcript levels of several
MMPs are significantly up-regulated, whereas tissue inhibitors of
MMPs are down-regulated, in dystrophic muscle of mdx mice. Chronic administration of
batimastat (BB-94), a broad spectrum
peptide inhibitor of
MMPs, reduced
necrosis, infiltration of macrophages, centronucleated fibers, and the expression of embryonic
myosin heavy chain in skeletal muscle of mdx mice.
Batimastat also reduced the expression of several inflammatory molecules and augmented the levels of sarcolemmal
protein beta-dystroglycan and neuronal
nitric oxide in mdx mice. In addition, muscle force production in isometric contraction was increased in
batimastat-treated mdx mice compared with those treated with vehicle alone. Furthermore, inhibition of
MMPs using
batimastat reduced the activation of
mitogen-activated protein kinases and
activator protein-1 in myofibers of mdx mice. Our study provides the novel evidence that the expression of
MMPs is atypically increased in DMD, that their inhibition ameliorates pathogenesis, and that
batimastat could prove to be a significant candidate for DMD
therapy.