Genetic ablation of complement C3 attenuates muscle pathology in dysferlin-deficient mice

Renzhi Han; Ellie M Frett; Jennifer R Levy; Erik P Rader; John D Lueck; Dimple Bansal; Steven A Moore; Rainer Ng; Daniel Beltrán-Valero de Bernabé; John A Faulkner; Kevin P Campbell

doi:10.1172/JCI42390

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Genetic ablation of complement C3 attenuates muscle pathology in dysferlin-deficient mice

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Genetic ablation of complement C3 attenuates muscle pathology in dysferlin-deficient mice

Renzhi Han, Ellie M Frett, Jennifer R Levy, Erik P Rader, John D Lueck, Dimple Bansal, Steven A Moore, Rainer Ng, Daniel Beltrán-Valero de Bernabé, John A Faulkner, …

The Journal of clinical investigation, Vol.120(12), pp.4366-4374

12/01/2010

DOI: 10.1172/JCI42390

PMCID: PMC2993587

PMID: 21060153

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Abstract

Mutations in the dysferlin gene underlie a group of autosomal recessive muscle-wasting disorders denoted as dysferlinopathies. Dysferlin has been shown to play roles in muscle membrane repair and muscle regeneration, both of which require vesicle-membrane fusion. However, the mechanism by which muscle becomes dystrophic in these disorders remains poorly understood. Although muscle inflammation is widely recognized in dysferlinopathy and dysferlin is expressed in immune cells, the contribution of the immune system to the pathology of dysferlinopathy remains to be fully explored. Here, we show that the complement system plays an important role in muscle pathology in dysferlinopathy. Dysferlin deficiency led to increased expression of complement factors in muscle, while muscle-specific transgenic expression of dysferlin normalized the expression of complement factors and eliminated the dystrophic phenotype present in dysferlin -null mice. Furthermore, genetic disruption of the central component (C3) of the complement system ameliorated muscle pathology in dysferlin -deficient mice but had no significant beneficial effect in a genetically distinct model of muscular dystrophy, mdx mice. These results demonstrate that complement-mediated muscle injury is central to the pathogenesis of dysferlinopathy and suggest that targeting the complement system might serve as a therapeutic approach for this disease.

Details

Title: Subtitle: Genetic ablation of complement C3 attenuates muscle pathology in dysferlin-deficient mice
Creators: Renzhi Han - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
Ellie M Frett - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
Jennifer R Levy - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
Erik P Rader - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
John D Lueck - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
Dimple Bansal - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
Steven A Moore - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
Rainer Ng - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
Daniel Beltrán-Valero de Bernabé - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
John A Faulkner - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
Kevin P Campbell - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.120(12), pp.4366-4374
DOI: 10.1172/JCI42390
PMID: 21060153
PMCID: PMC2993587
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: American Society for Clinical Investigation
Language: English
Date published: 12/01/2010
Academic Unit: Neurology; Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute
Record Identifier: 9984020871502771

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