Abstract
Mutations in the DYSF gene, encoding dysferlin, cause muscular dystrophies in man. We compared 4 dysferlinopathic mouse strains: SJL/J and B10.SJL-Dysfim/AwaJ (B10.SJL), and A/J and B6.A-Dysfprmd/GeneJ (B6.A/J). The former but not the latter two are overtly myopathic and weaker at 3 months of age. Following repetitive large-strain injury (LSI) caused by lengthening contractions, all except B6.A/J showed ~40% loss in contractile torque. Three days later, torque in SJL/J, B10.SJL and controls, but not A/J, recovered nearly completely. B6.A/J showed ~30% torque loss post-LSI and more variable recovery. Pre-injury, all dysferlinopathic strains had more centrally nucleated fibers (CNFs) and all but A/J showed more inflammation than controls. At D3, all dysferlinopathic strains showed increased necrosis and inflammation, but not more CNFs; controls were unchanged. Dystrophin-null DMDmdx mice showed more necrosis and inflammation than all dysferlin-nulls. Torque loss and inflammation on D3 across all strains were linearly related to necrosis. Our results suggest that (1) dysferlin is not required for functional recovery 3 days after LSI; (2) B6.A/J mice recover from LSI erratically; (3) SJL/J and B10.SJL muscles recover rapidly, perhaps due to ongoing myopathy; (4) although they recover function to different levels, all 4 dysferlinopathic strains show increased inflammation and necrosis 3 days after LSI.
Highlights
The DYSF gene encodes dysferlin, a tail-anchored integral membrane protein of 230 kDa that is thought to mediate membrane stability or fusion through the action of calciumbinding C2 domains in its large cytoplasmic region [1,2,3]
We used established physiological and morphological methods to compare 4 strains of dysferlin-deficient mice, A/J and SJL/J, which carry different mutations of dysferlin, and B6.A/J and B10.SJL, which carry their respective mutations in the C57Bl/6J and C57Bl/10J backgrounds
All dysferlinopathic strains and their controls were significantly weaker than deficient C57BL/10ScSnDmdmdx/J mice (DMDmdx) mice, consistent with earlier reports that the latter are stronger than controls [24,25,26]
Summary
The DYSF gene encodes dysferlin, a tail-anchored integral membrane protein of 230 kDa that is thought to mediate membrane stability or fusion through the action of calciumbinding C2 domains in its large cytoplasmic region [1,2,3]. There are currently no treatments for these diseases, but several therapeutic approaches have been tested in vitro and in mice, including gene therapeutic studies. The success of these experiments and their ultimate translation to the clinic will rely on the availability of murine models of the human dysferlinopathies. We report the results of comparative studies on the two spontaneously occurring murine dysferlin mutants, SJL/J and A/J, and of the two strains derived from these mutants by breeding them into C57Bl mice, B10.SJLDysfim/AwaJ and B6.A-Dysfprmd/GeneJ (referred to in this paper as B10.SJL and B6.A/J, resp.).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
