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Abstract
Objective: Neuronal nitric oxide synthase (nNOS), normally expressed at the sarcolemmal membrane, is known to be mislocalized to the sarcoplasm in several forms of muscular dystrophy. Our objectives were to characterize further the range of patients manifesting aberrant nNOS sarcolemmal immunolocalization and to study nNOS localization in animal models of nondystrophic myopathy.
Methods: We carried out a retrospective cross-sectional study. We performed immunofluorescent staining for nNOS on biopsy specimens from 161 patients with acquired and nondystrophin inherited neuromuscular conditions. The localization of sarcolemmal nNOS correlated with mobility and functional status. Muscle specimens from mouse models of steroid-induced and starvation-related atrophy were studied for qualitative and quantitative nNOS expression.
Results: Sarcolemmal nNOS staining was abnormal in 42% of patients with inherited myopathic conditions, 25% with acquired myopathic conditions, 57% with neurogenic conditions, and 93% with hypotonia. Interestingly, we found significant associations between mobility status or muscle function and sarcolemmal nNOS expression. Furthermore, mouse models of catabolic stress also demonstrated mislocalization of sarcolemmal nNOS.
Conclusion: Our analyses indicate that nNOS mislocalization is observed in a broad range of nondystrophic neuromuscular conditions associated with impaired mobility status and catabolic stress. Our findings suggest that the assessment of sarcolemmal localization of nNOS represents an important tool for the evaluation of muscle biopsies of patients with a variety of inherited and acquired forms of neuromuscular disorders.
Footnotes
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Study funding: R.D.C. is supported by the National Institutes of Health (NIH) Director's New Innovator Award DP2 OD004515, by NIH 5K08NS055879 award, and by the Muscular Dystrophy Association 101938. E.L.F.H. is supported by grant number 5KL2RR025006 from the National Center for Research Resources (NCRR), a component of the NIH, and the NIH Roadmap for Medical Research.
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- ALS
- amyotrophic lateral sclerosis
- CaM
- Ca2+ calmodulin
- cGMP
- cyclic guanosine monophosphate
- DGC
- dystrophin-glycoprotein complex
- eNOS
- endothelial nitric oxide synthase
- FoxO
- forkhead box, subgroup O
- iNOS
- inducible nitric oxide synthase
- IRB
- Institutional Review Board
- LGMD
- limb girdle muscular dystrophy
- nNOS
- neuronal nitric oxide synthase
- NO
- nitric oxide
- PDE5
- phosphodiesterase 5
- PFK
- phosphofructokinase
- SMA
- spinal muscular atrophy
Editorial, page 940
Supplemental data at www.neurology.org
- Received July 28, 2010.
- Accepted October 8, 2010.
- Copyright © 2011 by AAN Enterprises, Inc.
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