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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 4

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Inactivation of Bax improved soleus muscle histology. Frozen sections we...
Inactivation of Bax improved soleus muscle histology. Frozen sections were prepared from the leg muscles of 7-week-old mice of different genotypes, including wild-type mice (Lama2+/+Bax+/+, top row), laminin-α2_deficient mice with normal Bax (Lama2–/–Bax+/+, central row), and laminin-α2_deficient mice with no Bax (Lama2–/–Bax–/–, bottom row) as indicated. After staining with H&E, sections were examined at low (left column) and high (right column) magnification. In the left column, the soleus muscles are outlined to show that inactivation of Bax increased the overall size of the Lama2–/– soleus muscle, and the right column shows that inactivation of Bax also increased the cross-sectional areas of myofibers in Lama2–/– soleus muscle (see text and Figure 3 for quantitative measurements). Irrespective of Bax genotype, Lama2–/– soleus muscles had about the same number of mononucleate cells and myofibers with central nuclei. Scale bars: left column, 500 μm; right column, 100 μm.

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