Skeletal Muscle Blog

Dystrophin/dysferlin null mice as useful therapeutic models

It is well known that some forms of muscular dystrophies are caused by mutations in the genes coding for dystrophin and dysferlin – two proteins which both have important roles in the correct functioning of skeletal muscle.

The dystrophin protein is located in the plasma membrane of skeletal muscle, and is an integral part of the dystrophin-glycoprotein complex (DGC). The DGC forms a link between the sarcolemma (the muscle cell membrane) and the cytoskeleton thereby ensuring cell membrane stability and preventing damage during lengthening contractions of the muscle. Dysferlin on the other hand is known to play a critical role in calcium dependent membrane repair. A defect in either protein’s role has a detrimental effect on the muscle.

A new research article published this month in Skeletal Muscle uses dystrophin/dysferlin double knock-out (DKO) mice to look at how muscle pathology in dysferlin-null mice is exacerbated by an additional dystrophin deficiency. DKO mice show increased histopathology, decreased sarcolemmal integrity and severe functional defects. The double deficiency causes more severe muscular dystrophy than dysferlin-deficient or wild type mice, and also results in the mice being physically weaker, suffering from contraction-induced injuries and having a low force production. In addition, onset of the muscle pathology in mice lacking both dystrophin and dysferlin is earlier than in the dysferlin-deficient mice. 

Han et al. reveal that the role dysferlin has in repairing damaged membranes can be unmasked by a dystrophin deficiency. In dystrophin deficient mice, the initial injury caused by lengthening muscle contractions is more severe than in wild type and dysferlin-null mice. Dystrophin deficient mice are however capable of recovery, revealing the presence of an active membrane repair process to restore membrane integrity. Dysferlin mice on the other hand show a poor recovery, as do DKO mice. These results suggest that the DKO mouse model may be useful in the development of therapies designed to treat dysferlinopathies – muscular dystrophies caused by a defect in the function of the dysferlin protein.

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Posted at 04:13PM Dec 06, 2011 by Laura Winton in General  |  Comments[0]