Dystrophin and utrophin influence fiber type composition and post-synapticmembrane structure

The X-linked muscle wasting disease Duchenne muscular dystrophy is caused b y the lack of dystrophin in muscle. Protein structure predictions, patient mutations, in vitro binding studies and transgenic and knockout mice sugges t that dystrophin plays a mechanical role in skeletal muscle, linking the s ubsarcolemmal cytoskeleton with the extracellular matrix through its direct interaction with the dystrophin-associated protein complex (DAPC). Althoug h a signaling role for dystrophin has been postulated, definitive data have been lacking. To identify potential non-mechanical roles of dystrophin, we tested the ability of various truncated dystrophin transgenes to prevent a ny of the skeletal muscle abnormalities associated with the double knockout mouse deficient for both dystrophin and the dystrophin-related protein utr ophin. We show that restoration of the DAPC with Dp71 does not prevent the structural abnormalities of the post-synaptic membrane or the abnormal oxid ative properties of utrophin/dystrophin-deficient muscle. In marked contras t, a dystrophin protein lacking the cysteine-rich domain, which is unable t o prevent dystrophy in the mdx mouse, is able to ameliorate these abnormali ties in utrophin/dystrophin-deficient mice. These experiments provide the f irst direct evidence that in addition to a mechanical role and relocalizati on of the DAPC, dystrophin and utrophin are able to alter both structural a nd biochemical properties of skeletal muscle. In addition, these mice provi de unique insights into skeletal muscle fiber type composition.