Differential roles of MMP-9 in early and late stages of dystrophic muscles in a mouse model of Duchenne muscular dystrophy

Naoko Shiba; Daigo Miyazaki; Takahiro Yoshizawa; Kazuhiro Fukushima; Yuji Shiba; Yuji Inaba; Michihiro Imamura; Shin'ichi Takeda; Kenichi Koike; Akinori Nakamura

doi:10.1016/j.bbadis.2015.07.008

Differential roles of MMP-9 in early and late stages of dystrophic muscles in a mouse model of Duchenne muscular dystrophy

Biochim Biophys Acta. 2015 Oct;1852(10 Pt A):2170-82. doi: 10.1016/j.bbadis.2015.07.008. Epub 2015 Jul 10.

Authors

Affiliations

¹ Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
² Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
³ Division of Laboratory Animal Research, Research Center for Human and Environmental Sciences, Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
⁴ Intractable Disease Care Center, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
⁵ Department of Cardiovascular Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
⁶ Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira 187-8561, Japan.
⁷ Intractable Disease Care Center, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto 390-8621, Japan. Electronic address: anakamu@shinshu-u.ac.jp.

PMID: 26170062
DOI: 10.1016/j.bbadis.2015.07.008

Abstract

Matrix metalloprotease (MMP)-9 is an endopeptidase associated with the pathogenesis of Duchenne muscular dystrophy (DMD). The precise function of MMP-9 in DMD has not been elucidated to date. We investigated the effect of genetic ablation of MMP-9 in the mdx mouse model (mdx/Mmp9(-/-)). At the early disease stage, the muscles of mdx/Mmp9(-/-) mice showed reduced necrosis and neutrophil invasion, accompanied by down-regulation of chemokine MIP-2. In addition, muscle regeneration was enhanced, which coincided with increased macrophage infiltration and upregulation of MCP-1, and resulted in increased muscle strength. The mdx/Mmp9(-/-) mice also displayed accelerated upregulation of osteopontin expression in skeletal muscle at the acute onset phase of dystrophy. However, at a later disease stage, the mice exhibited muscle growth impairment through altered expression of myogenic factors, and increased fibroadipose tissue. These results showed that MMP-9 might have multiple functions during disease progression. Therapy targeting MMP-9 may improve muscle pathology and function at the early disease stage, but continuous inhibition of this protein may result in the accumulation of fibroadipose tissues and reduced muscle strength at the late disease stage.

Keywords: Dystrophin; Fibrosis; MCP-1; MIP-2; MMP-9; Osteopontin.