Loss of
dystrophin protein due to mutations in the DMD gene causes
Duchenne muscular dystrophy.
Dystrophin loss also leads to the loss of the
dystrophin glycoprotein complex (DGC) from the sarcolemma which contributes to the dystrophic phenotype.
Tyrosine phosphorylation of
dystroglycan has been identified as a possible signal to promote the proteasomal degradation of the DGC. In order to test the role of
tyrosine phosphorylation of
dystroglycan in the aetiology of DMD, we generated a knock-in mouse with a
phenylalanine substitution at a key
tyrosine phosphorylation site in
dystroglycan, Y890.
Dystroglycan knock-in mice (Dag1(Y890F/Y890F)) had no overt phenotype. In order to examine the consequence of blocking
dystroglycan phosphorylation on the aetiology of
dystrophin-deficient
muscular dystrophy, the Y890F mice were crossed with mdx mice an established model of
muscular dystrophy. Dag1(Y890F/Y890F)/mdx mice showed a significant improvement in several parameters of muscle pathophysiology associated with
muscular dystrophy, including a reduction in centrally nucleated fibres, less
Evans blue dye infiltration and lower serum
creatine kinase levels. With the exception of
dystrophin, other DGC components were restored to the sarcolemma including α-
sarcoglycan, α-/β-
dystroglycan and sarcospan. Furthermore, Dag1(Y890F/Y890F)/mdx showed a significant resistance to muscle damage and force loss following repeated eccentric contractions when compared with mdx mice. While the Y890F substitution may prevent
dystroglycan from proteasomal degradation, an increase in sarcolemmal
plectin appeared to confer protection on Dag1(Y890F/Y890F)/mdx mouse muscle. This new model confirms
dystroglycan phosphorylation as an important pathway in the aetiology of DMD and provides novel targets for therapeutic intervention.