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Human Molecular Genetics Advance Access originally published online on January 8, 2009
Human Molecular Genetics 2009 18(7):1209-1220; doi:10.1093/hmg/ddp015
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Sub-physiological sarcoglycan expression contributes to compensatory muscle protection in mdx mice

Dejia Li, Chun Long, Yongping Yue and Dongsheng Duan*

Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, MO, USA

* To whom correspondence should be addressed at: Department of Molecular Microbiology and Immunology, One Hospital Dr., Columbia, MO 65212, USA. Tel: +1 5738849584; Fax: +1 5738824287; Email: duand{at}missouri.edu

Received December 6, 2008; Revised December 31, 2008; Accepted January 6, 2009

Sarcoglycans are a group of single-pass transmembrane glycoproteins. In striated muscle, sarcoglycans interact with dystrophin and other dystrophin-associated proteins (DAPs) to form the dystrophin-associated glycoprotein complex (DGC). The DGC protects the sarcolemma from contraction-induced injury. Duchenne muscular dystrophy (DMD) is caused by dystrophin gene mutations. In the absence of dystrophin, the DGC is disassembled from the sarcolemma. This initiates a chain reaction of muscle degeneration, necrosis, inflammation and fibrosis. In contrast to human patients, dystrophin-null mdx mice are only mildly affected. Enhanced muscle regeneration and the up-regulation of utrophin and integrin are thought to protect mdx muscle. Interestingly, trace amounts of sarcoglycans and other DAPs can be detected at the mdx sarcolemma. It is currently unclear whether sub-physiological sarcoglycan expression also contributes to the mild phenotype in mdx mice. To answer this question, we generated {delta}-sarcoglycan/dystrophin double knockout mice ({delta}-Dko) in which residual sarcoglycans were completely eliminated from the sarcolemma. Interestingly, utrophin levels were further increased in these mice. However, enhanced utrophin expression did not mitigate disease. The clinical manifestation of {delta}-Dko mice was worse than that of mdx mice. They showed characteristic dystrophic signs, body emaciation and more macrophage infiltration. Their lifespan was reduced by 60%. Furthermore, {delta}-Dko muscle generated significantly less absolute muscle force and became more susceptible to contraction-induced injury. Our results suggest that sub-physiological sarcoglycan expression plays a critical role in ameliorating muscle disease in mdx mice. We speculate that low-level sarcoglycan expression may represent a useful strategy to palliate DMD.


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