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Published 1 October 2001. doi:10.1083/jcb.200105110
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© The Rockefeller University Press, 0021-9525/2001/10/123 $5.00
The Journal of Cell Biology, Volume 155, Number 1, October 1, 2001 123-132

Article

A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice



Michelle Wehling1, Melissa J. Spencer2 and James G. Tidball1,3

1 Department of Physiological Science, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095
2 Department of Pediatrics, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095
3 Department of Pathology and Laboratory Medicine, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095

Address correspondence to James G. Tidball, Department of Physiological Science, University of California at Los Angeles, 5833 Life Science Building, Los Angeles, CA 90095. Tel.: (310) 206-3395. Fax: (310) 206-8389. E-mail: jtidball{at}physci.ucla.edu

Dystrophin-deficient muscles experience large reductions in expression of nitric oxide synthase (NOS), which suggests that NO deficiency may influence the dystrophic pathology. Because NO can function as an antiinflammatory and cytoprotective molecule, we propose that the loss of NOS from dystrophic muscle exacerbates muscle inflammation and fiber damage by inflammatory cells. Analysis of transgenic mdx mice that were null mutants for dystrophin, but expressed normal levels of NO in muscle, showed that the normalization of NO production caused large reductions in macrophage concentrations in the mdx muscle. Expression of the NOS transgene in mdx muscle also prevented the majority of muscle membrane injury that is detectable in vivo, and resulted in large decreases in serum creatine kinase concentrations. Furthermore, our data show that mdx muscle macrophages are cytolytic at concentrations that occur in dystrophic, NOS-deficient muscle, but are not cytolytic at concentrations that occur in dystrophic mice that express the NOS transgene in muscle. Finally, our data show that antibody depletions of macrophages from mdx mice cause significant reductions in muscle membrane injury. Together, these findings indicate that macrophages promote injury of dystrophin-deficient muscle, and the loss of normal levels of NO production by dystrophic muscle exacerbates inflammation and membrane injury in muscular dystrophy.

Key Words: muscle; muscular dystrophy; nitric oxide synthase; macrophages; inflammation


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