Distinct Effects of Contraction-Induced Injury In Vivo on Four Different Murine Models of Dysferlinopathy

الملخص EN

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.