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.

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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