Preventing phosphorylation of dystroglycan ameliorates the dystrophic phenotype in mdx mouse

Miller, G; Moore, C J; Terry, R L; La Riviere, T; Mitchell, A; Piggott, R; Dear, T N; Wells, D J; Winder, S J

Abstract

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 (Dag1Y890F/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. Dag1Y890F/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, Dag1Y890F/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 Dag1Y890F/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.

Citation

Miller, G., Moore, C. J., Terry, R. L., La Riviere, T., Mitchell, A., Piggott, R., …Winder, S. J. (in press). Preventing phosphorylation of dystroglycan ameliorates the dystrophic phenotype in mdx mouse. Human Molecular Genetics, 21(20), 4508-4520. https://doi.org/10.1093/hmg/dds293

• Journal Article Type: Article
• Acceptance Date: Jul 13, 2012
• Deposit Date: Nov 11, 2014
• Publicly Available Date: Jan 14, 2019
• Journal: HUMAN MOLECULAR GENETICS
• Print ISSN: 0964-6906
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 21
• Issue: 20
• Pages: 4508-4520
• DOI: https://doi.org/10.1093/hmg/dds293
• Public URL: https://rvc-repository.worktribe.com/output/1413184
• Additional Information: Corporate Creators : Sheffield