Dysferlin overexpression in skeletal muscle produces a progressive myopathy
Article first published online: 30 NOV 2009
Copyright © 2010 American Neurological Association
Annals of Neurology
Volume 67, Issue 3, pages 384–393, March 2010
How to Cite
Glover, L. E., Newton, K., Krishnan, G., Bronson, R., Boyle, A., Krivickas, L. S. and Brown, R. H. (2010), Dysferlin overexpression in skeletal muscle produces a progressive myopathy. Ann Neurol., 67: 384–393. doi: 10.1002/ana.21926
- Issue published online: 29 MAR 2010
- Article first published online: 30 NOV 2009
- Accepted manuscript online: 30 NOV 2009 12:00AM EST
- Manuscript Accepted: 6 NOV 2009
- Manuscript Revised: 3 NOV 2009
- Manuscript Received: 26 JAN 2009
- CB Day Company
- NIH (National Institute of Neurological Diseases and Stroke)
- Muscular Dystrophy Association. Grant Number: MDA 4062
The dose–response effects of dysferlin transgenesis were analyzed to determine if the dysferlin-deficient myopathies are good candidates for gene replacement therapy.
We have generated 3 lines of transgenic mice, expressing low, mid, and high levels of full-length human dysferlin from a muscle-specific promoter. Transgenic skeletal muscle was analyzed and scored for morphological and functional deficits.
Overexpression of dysferlin in mice resulted in a striking phenotype of kyphosis, irregular gait, and reduced muscle mass and strength. Moreover, protein dosage correlated with phenotype severity. In contrast to dysferlin-null skeletal muscle, no evidence of sarcolemmal impairment was revealed. Rather, increased levels of Ca2+-regulated, dysferlin-binding proteins and endoplasmic reticulum stress chaperone proteins were observed in muscle lysates from transgenic mice as compared with controls.
Expression levels of dysferlin are important for appropriate function without deleterious or cytotoxic effects. As a corollary, we propose that future endeavors in gene replacement for correction of dysferlinopathy should be tailored to take account of this. ANN NEUROL 2010;67:384–393