Matrix metalloproteinase inhibitor batimastat alleviates pathology and improves skeletal muscle function in dystrophin-deficient mdx mice.
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.
Kumar
Akhilesh
A
Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, 500 South Preston Street, Louisville, KY 40202, USA.
Bhatnagar
Shephali
S
Kumar
Ashok
A
D000818:Animals; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000502:physiology*; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000503:physiopathology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use; D018808:Transcription Factor AP-1 / Q000378:metabolism
D016189:Dystrophin; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013876:Thiophenes; D018808:Transcription Factor AP-1; D010649:Phenylalanine; C080985:batimastat; D020928:Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases
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