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Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy
Mahasweta Girgenrath, … , Christine A. Kostek, Jeffrey Boone Miller
Mahasweta Girgenrath, … , Christine A. Kostek, Jeffrey Boone Miller
Published December 1, 2004
Citation Information: J Clin Invest. 2004;114(11):1635-1639. https://doi.org/10.1172/JCI22928.
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Article Neuroscience

Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy

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Abstract

The most common form of human congenital muscular dystrophy (CMD) is caused by mutations in the laminin-α2 gene. Loss of laminin-α2 function in this autosomal recessive type 1A form of CMD results in neuromuscular dysfunction and, often, early death. Laminin-α2–deficient skeletal muscles in both humans and mice show signs of muscle cell death by apoptosis. To examine the significance of apoptosis in CMD1A pathogenesis, we determined whether pathogenesis in laminin-α2–deficient (Lama2–/–) mice could be ameliorated by inhibiting apoptosis through either (a) inactivation of the proapoptosis protein Bax or (b) overexpression of the antiapoptosis protein Bcl-2 from a muscle-specific transgene. We found that both of these genetic interventions produced a several-fold increase in the lifespan of Lama2–/– mice. Bax inactivation also improved postnatal growth rate and myofiber histology and decreased fixed contractures of Lama2–/– mice. Thus, Bcl-2 family–mediated apoptosis contributes significantly to pathogenesis in the mouse model of CMD1A, and antiapoptosis therapy may be a possible route to amelioration of neuromuscular dysfunction due to laminin-α2 deficiency in humans.

Authors

Mahasweta Girgenrath, Janice A. Dominov, Christine A. Kostek, Jeffrey Boone Miller

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Figure 2

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(A) Diagram of the cDNA used to produce pMyoD-hBcl-2 transgenic mice in ...
(A) Diagram of the cDNA used to produce pMyoD-hBcl-2 transgenic mice in which an approximately 7-kb fragment of the mouse MyoD promoter was used to drive expression of full-length human Bcl-2 (hBcl-2) cDNA. Arrows show locations of genotyping PCR primers. SV40, simian virus 40 splicing sequence. (B) Transgene expression is skeletal-muscle specific. As indicated, Ab’s specific for transgenic human Bcl-2 or endogenous mouse Bcl-2 were used to probe Western blots of protein extracts made from tissues of wild-type or transgenic mice. Human Bcl-2 was expressed only in skeletal muscles (LM, leg muscles; Di, diaphragm) of transgenic mice; it was not expressed in skeletal muscles of wild-type mice or in nonmuscle tissues (Kd, kidney; Br, brain; Ht, heart) of transgenic mice. The endogenous mouse Bcl-2 was expressed in thymus (Th) and spleen (Sp) of wild-type mice, but was not detectable in skeletal muscles of either wild-type or transgenic mice or in heart and liver (Lv) of transgenic mice. (C) Myotubes formed in culture from myoblasts derived from 3-week-old pMyoD-hBcl-2 leg muscles were more resistant to cell death induced by 100 nM staurosporine measured by propidium iodide (PI) permeability than those formed by wild-type myoblasts.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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