title: Elevated levels of active matrix metalloproteinase-9 cause hypertrophy in skeletal muscle of normal and dystrophin-deficient mdx mice.
abstract: Matrix metalloproteinases (MMPs) are a group of extracellular proteases involved in tissue remodeling in several physiological and pathophysiological conditions. While increased expression of MMPs (especially MMP-9) has been observed in skeletal muscle in numerous conditions, their physiological significance remains less-well understood. By generating novel skeletal muscle-specific transgenic (Tg) mice expressing constitutively active mutant of MMP-9 (i.e. MMP-9G100L), in this study, we have investigated the effects of elevated levels of MMP-9 on skeletal muscle structure and function in vivo. Tg expression of enzymatically active MMP-9 protein significantly increased skeletal muscle fiber cross-section area, levels of contractile proteins and force production in isometric contractions. MMP-9 stimulated the activation of the Akt signaling pathway in Tg mice. Moreover, expression of active MMP-9 increased the proportion of fast-type fiber in soleus muscle of mice. Overexpression of MMP-9 also considerably reduced the deposition of collagens I and IV in skeletal muscle in vivo. In one-year-old mdx mice (a model for Duchenne muscular dystrophy, DMD), deletion of the Mmp9 gene reduced fiber hypertrophy and phosphorylation of Akt and p38 mitogen-activated protein kinase. Collectively, our study suggests that elevated levels of active MMP-9 protein cause hypertrophy in skeletal muscle and that the modulation of MMP-9 levels may have therapeutic value in various muscular disorders including DMD.
authors.affiliation: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Dahiya
authors.forename: Shephali
authors.initials: S
authors.lastname: Bhatnagar
authors.forename: Sajedah M
authors.initials: SM
authors.lastname: Hindi
authors.forename: Chunhui
authors.initials: C
authors.lastname: Jiang
authors.forename: Pradyut K
authors.initials: PK
authors.lastname: Paul
authors.forename: Shihuan
authors.initials: S
authors.lastname: Kuang
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000818:Animals; D016189:Dystrophin / Q000172:deficiency* / Q000235:genetics; D005260:Female; D006984:Hypertrophy / Q000378:metabolism* / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*
chemical_list: D016189:Dystrophin; D020780:Matrix Metalloproteinase 9