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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 3

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Inactivation of Bax improved Lama2–/– muscles. (A) Exploratory behavior,...
Inactivation of Bax improved Lama2–/– muscles. (A) Exploratory behavior, measured by the number of times mice stood up on their hind legs during the first 5 minutes in a new cage, was much decreased in 6-week-old Lama2–/–Bax+/+ mice (red bar), compared with wild-type Lama2+/+Bax+/+ mice (WT, black bar). When Bax was inactivated in Lama2–/– mice, in contrast, the Lama2–/–Bax–/– mice (green bar) showed exploratory behavior that was near that of wild-type. Error bars = SE; n = 3 for Lama2–/–Bax+/+ mice and n = 4 for WT and Lama2–/–Bax–/– mice. (B) The mass of individual Lama2–/– muscles was increased by inactivation of Bax. The gastrocnemius/soleus (G/S), tibialis anterior (TA), and quadriceps (Quad) muscles weighed more in Lama2–/–Bax–/– mice (green bars) than in Lama2–/–Bax+/+ mice (red bars). Data are plotted as percentage of wild-type (Lama2-positive, Bax-positive) values. Error bars = SE; n = 3_11. (C) The size of myofibers in Lama2–/– muscles was increased by inactivation of Bax. In the soleus muscle, both fast and slow myofibers had larger mean cross-sectional areas in Lama2–/–Bax–/– mice (green bars) than in Lama2–/–Bax+/+ mice (red bars). Data are plotted as percentage of wild-type (Lama2-positive, Bax-positive) values. Error bars = SE; n = 3_5. In all panels, the Bax-positive and Bax-null samples were significantly different at P < 0.05 (t test using primary data prior to conversion to percentage of wild-type).

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

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