Ku70 improves MDC1A pathology

Ku70 which regulates Bax ( a regulator of cell apoptosis) helps improve MDC1A muscle cells and mouse

Hum Mol Genet. 2009 Aug 19. [Epub ahead of print]

Ku70 regulates Bax-mediated pathogenesis in laminin-{alpha}2-deficient human muscle cells and mouse models of congenital muscular dystrophy.

Vishnudas VK, Miller JB.

Neuromuscular Biology & Disease Group and.

The severely debilitating disease Congenital Muscular Dystrophy Type 1A (MDC1A) is caused by mutations in the gene encoding laminin-alpha2. Bax-mediated muscle cell death is a significant contributor to the severe neuromuscular pathology seen in the Lama2-null mouse model of MDC1A. To extend our understanding of pathogenesis due to laminin-alpha2-deficiency, we have now analyzed molecular mechanisms of Bax regulation in normal and laminin-alpha2-deficient muscles and cells, including myogenic cells obtained from patients with a clinical diagnosis of MDC1A. In mouse myogenic cells, we found that, as in non-muscle cells, Bax co-immunoprecipitated with the multifunctional protein Ku70. In addition, cell permeable pentapeptides designed from Ku70, termed Bax-inhibiting peptides (BIPs), inhibited staurosporine-induced Bax translocation and cell death in mouse myogenic cells. We also found that acetylation of Ku70, which can inhibit binding to Bax and can be an indicator of increased susceptibility to cell death, was more abundant in Lama2-null than in normal mouse muscles. Furthermore, myotubes formed in culture from human laminin-alpha2-deficient patient myoblasts produced high levels of activated caspase-3 when grown on poly-L-lysine, but not when grown on a laminin-alpha2-containing substrate or when treated with BIPs. Finally, cytoplasmic Ku70 in human laminin-alpha2-deficient myotubes was both reduced in amount and more highly acetylated than in normal myotubes. Increased susceptibility to cell death thus appears to be an intrinsic property of human laminin-alpha2-deficient myotubes. These results identify Ku70 as a regulator of Bax-mediated pathogenesis and a therapeutic target in laminin-alpha2-deficiency.

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  • Congenital Muscular Dystrophy

    A group of diseases causing muscle weakness at birth. Several defined genetic mutations cause muscles to break down faster than they can repair or grow. A child with CMD may have various neurological or physical impairments. Some children never gain the ability to walk, while others lose the ability as they grow older. Learn more...

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