title: Diaphragm displays early and progressive functional deficits in dysferlin-deficient mice.
abstract: Mouse lines with dysferlin deficiency are accepted animal models for limb girdle muscular dystrophy 2B and Miyoshi myopathy, yet slow progression of pathology prevents rapid screening of potential therapies for this disease. Our goal was to define a functional signature for skeletal muscles that lack dysferlin. Force generation and susceptibility to eccentric contractile injury measurements were performed in isolated limb muscles and the diaphragm from 10- and 36-week-old A/J and age-matched control mice. Limb muscles had normal specific force at both 10 and 36 weeks, whereas the diaphragm had significant deficits in both specific force and susceptibility to eccentric contractile injury. Membrane ruptures in the diaphragm during eccentric contractions occurred predominantly in myosin heavy chain 2A-expressing fibers. Dysferlin content did not vary significantly between wildtype muscles, suggesting that there was no correlation between disease severity and normal endogenous levels of the protein. These studies show that, unlike limb muscles, the diaphragm from the A/J mouse displays early deficits in function that may lower the age needed for evaluating potential therapies for dysferlinopathies.
authors.affiliation: Department of Anatomy and Cell Biology, School of Dental Medicine, 441A Levy Building, 240 S. 40th Street, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. erbarton@biochem.dental.upenn.edu
authors.forename: Elisabeth R
authors.initials: ER
authors.lastname: Barton
authors.forename: Bing Jing
authors.initials: BJ
authors.lastname: Wang
authors.forename: Becky K
authors.initials: BK
authors.lastname: Brisson
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003964:Diaphragm / Q000473:pathology / Q000503:physiopathology*; D000073939:Dysferlin; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D007537:Isometric Contraction / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000473:pathology
chemical_list: C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins