Ku70 regulates Bax-mediated pathogenesis in laminin-alpha2-deficient human muscle cells and mouse models of congenital muscular dystrophy

UMMS Affiliation

Wellstone Center for FSHD



Document Type


Medical Subject Headings

Acetylation; Adult; Animals; Antigens, Nuclear; Cells, Cultured; DNA-Binding Proteins; Disease Models, Animal; Female; Humans; Infant; Lamin Type A; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Dystrophies; Protein Binding; Young Adult; bcl-2-Associated X Protein


Cell Biology | Developmental Biology | Molecular Biology | Molecular Genetics | Musculoskeletal Diseases | Nervous System Diseases


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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Citation: Vishnudas VK, Miller JB. Ku70 regulates Bax-mediated pathogenesis in laminin-alpha2-deficient human muscle cells and mouse models of congenital muscular dystrophy. Hum Mol Genet. 2009 Dec 1;18(23):4467-77. doi:10.1093/hmg/ddp399. Link to article on publisher's site

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