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?1D chain increases ?7?1 integrin and laminin and protects against sarcolemmal damage in mdx mice.

ABSTRACT: The dystrophin-glycoprotein complex connects myofibers with extracellular matrix laminin. In Duchenne muscular dystrophy, this linkage system is absent and the integrity of muscle fibers is compromised. One potential therapy for addressing muscular dystrophy is to augment the amount of ?7?1 integrin, the major laminin-binding integrin in skeletal muscle. Whereas transgenic over-expression of ?7 chain may alleviate development of muscular dystrophy and extend the lifespan of severely dystrophic mdx/utrn(-/-) mice, further enhancing levels of ?7 chain provided little additional membrane integrin and negligible additional improvement in mdx mice. We demonstrate here that normal levels of ?1 chain limit formation of integrin heterodimer and that increasing ?1D chain in mdx mice results in more functional integrin at the sarcolemma, more matrix laminin and decreased damage of muscle fibers. Moreover, increasing the amount of ?1D chain in vitro enhances transcription of ?7 integrin and ?2 laminin genes and the amounts of these proteins. Thus manipulation of ?1D integrin expression offers a novel approach to enhance integrin-mediated therapy for muscular dystrophy.

SUBMITTER: Liu J

PROVIDER: S-EPMC3298282 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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β1D chain increases α7β1 integrin and laminin and protects against sarcolemmal damage in mdx mice.

Liu Jianming J Milner Derek J DJ Boppart Marni D MD Ross Robert S RS Kaufman Stephen J SJ

Human molecular genetics 20111216 7

The dystrophin-glycoprotein complex connects myofibers with extracellular matrix laminin. In Duchenne muscular dystrophy, this linkage system is absent and the integrity of muscle fibers is compromised. One potential therapy for addressing muscular dystrophy is to augment the amount of α7β1 integrin, the major laminin-binding integrin in skeletal muscle. Whereas transgenic over-expression of α7 chain may alleviate development of muscular dystrophy and extend the lifespan of severely dystrophic m ...[more]

PMID: 22180459

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Project description:Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disease characterized by symptoms attributable to the death of striatal and cortical neurons. The molecular mechanisms mediating neuronal death in HD involve oxidative stress and mitochondrial dysfunction. Administration of 3-nitropropionic acid (3-NP), an irreversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, in rodents has been proposed as a useful experimental model of HD. This study evaluated the effects of probucol, a lipid-lowering agent with anti-inflammatory and antioxidant properties, on the biochemical parameters related to oxidative stress, as well as on the behavioral parameters related to motor function in an in vivo HD model based on 3-NP intoxication in rats. Animals were treated with 3.5 mg/kg of probucol in drinking water daily for 2 months and, subsequently, received 3-NP (25 mg/kg i.p.) once a day for 6 days. At the end of the treatments, 3-NP-treated animals showed a significant decrease in body weight, which corresponded with impairment on motor ability, inhibition of mitochondrial complex II activity and oxidative stress in the striatum. Probucol, which did not rescue complex II inhibition, protected against behavioral and striatal biochemical changes induced by 3-NP, attenuating 3-NP-induced motor impairments and striatal oxidative stress. Importantly, probucol was able to increase activity of glutathione peroxidase (GPx), an enzyme important in mediating the detoxification of peroxides in the central nervous system. The major finding of this study was that probucol protected against 3-NP-induced behavioral and striatal biochemical changes without affecting 3-NP-induced mitochondrial complex II inhibition, indicating that long-term probucol treatment resulted in an increased resistance against neurotoxic events (i.e., increased oxidative damage) secondary to mitochondrial dysfunction. These data appeared to be of great relevance when extrapolated to human neurodegenerative processes involving mitochondrial dysfunction and indicates that GPx is an important molecular target involved in the beneficial effects of probucol.

Dataset Information

?1D chain increases ?7?1 integrin and laminin and protects against sarcolemmal damage in mdx mice.

Publications

β1D chain increases α7β1 integrin and laminin and protects against sarcolemmal damage in mdx mice.

Similar Datasets

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