A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice
Open accessAbstract
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.
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In vivo, the response to muscle injury includes a significant number of infiltrating inflammatory cells, which can exceed 100,000 cells/mm3 of tissue.
“In vivo, however, the response following muscle tissue injury has been shown to include a significant number of infiltrating inflammatory cells which can exceed 100,000 cells/mm3 of tissue [111].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [111]
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- Authors
- Wehling, M., Spencer, M. J., & Tidball, J. G.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Wehling, Michelle
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2001-10-01
- Volume
- 155
- Issue
- 1
- Pages
- 123-132
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2150800
- OpenAlex
- W2126792732
- Cited by
- 530
- References
- 43
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 12 · 2023: 8 · 2022: 13 · 2021: 12 · 2020: 20 · 2019: 14 · 2018: 21 · 2017: 19 · 2016: 23 · 2015: 25 · 2014: 32 · 2013: 22 · 2012: 33
- FWCI
- 8.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Health Sciences › Medicine › Epidemiology › Inflammatory Myopathies and Dermatomyositis
- Keywords
- nitric oxide synthase, muscular dystrophy, mdx mice, dystrophin deficiency, macrophages, muscle inflammation, creatine kinase, macrophage cytotoxicity, macrophage depletion, transgenic rescue, anti-inflammatory therapy
- MeSH terms
- Animals, Creatine Kinase, Disease Models, Animal, Humans, Macrophages, Mice, Transgenic, Dystrophin, Mice, Inbred mdx, Muscle, Skeletal, Muscle Fibers, Skeletal, Nitric Oxide Synthase, Transgenes, Muscular Dystrophy, Duchenne, Mice, Nitric Oxide Synthase Type I
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