Sarcolemmal nNOS anchoring reveals a qualitative difference between dystrophin and utrophin
- 15 June 2010
- journal article
- Published by The Company of Biologists in Journal of Cell Science
- Vol. 123 (12), 2008-2013
- https://doi.org/10.1242/jcs.064808
Abstract
Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by dystrophin deficiency. In normal muscle, dystrophin helps maintain sarcolemmal stability. Dystrophin also recruits neuronal nitric oxide synthase (nNOS) to the sarcolemma. Failure to anchor nNOS to the membrane leads to functional ischemia and aggravates muscle disease in DMD. Over the past two decades, a great variety of therapeutic modalities have been explored to treat DMD. A particularly attractive approach is to increase utrophin expression. Utrophin shares considerable sequence, structural and functional similarity with dystrophin. Here, we test the hypothesis that utrophin also brings nNOS to the sarcolemma. Full-length utrophin cDNA was expressed in dystrophin-deficient mdx mice by gutted adenovirus or via transgenic overexpression. Subcellular nNOS localization was determined by immunofluorescence staining, in situ nNOS activity staining and microsomal preparation western blot. Despite supra-physiological utrophin expression, we did not detect nNOS at the sarcolemma. Furthermore, transgenic utrophin overexpression failed to protect mdx muscle from exercise-associated injury. Our results suggest that full-length utrophin cannot anchor nNOS to the sarcolemma. This finding might have important implications for the development of utrophin-based DMD therapies.Keywords
This publication has 50 references indexed in Scilit:
- Functional Substitution by TAT-Utrophin in Dystrophin-Deficient MicePLoS Medicine, 2009
- Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophyJCI Insight, 2009
- Sub-physiological sarcoglycan expression contributes to compensatory muscle protection in mdx miceHuman Molecular Genetics, 2009
- Sarcolemma-localized nNOS is required to maintain activity after mild exerciseNature, 2008
- Functional Deficits in nNOSμ-Deficient Skeletal Muscle: Myopathy in nNOS Knockout MicePLOS ONE, 2008
- Microutrophin Delivery Through rAAV6 Increases Lifespan and Improves Muscle Function in Dystrophic Dystrophin/Utrophin-deficient MiceMolecular Therapy, 2008
- Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophyNeurobiology of Disease, 2008
- Preservation of Muscle Force in Mdx3cv Mice Correlates with Low-Level Expression of a Near Full-Length Dystrophin ProteinThe American Journal of Pathology, 2008
- Pharmacological strategies for muscular dystrophyNature Reviews Drug Discovery, 2003
- Dystrophin and utrophin: the missing links!FEBS Letters, 1995