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

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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Inactivation of Bax eliminated early death and improved growth of lamini...
Inactivation of Bax eliminated early death and improved growth of laminin-α2_deficient Lama2–/– mice. (A) Survival curves for Lama2–/– mice show that most Lama2–/–Bax+/+ mice died within 2 months of birth, whereas lifespan was modestly increased in heterozygous Lama2–/–Bax+/– mice, and early death was completely eliminated in Lama2–/–Bax–/– mice. (B) Pictured at 6 weeks after birth, a Lama2–/–Bax–/– mouse (center) was much larger than a Lama2–/–Bax+/+ mouse (left), though not so large as a wild-type Lama2+/+Bax+/+ mouse (right). Contractures of hind limbs (arrow) developed in Lama2–/–Bax–/– mice during the first 2_3 months of life but did not develop on Lama2–/–Bax–/– or wild-type mice. (C) Growth curves show that the postweaning growth rate of Lama2–/– mice was significantly increased by inactivation of Bax, through growth of Lama2–/–Bax–/– mice lagged behind that of healthy Lama2+/+ wild-type mice. Error bars = SE; n = 5_15. The mean body weights of Lama2–/–Bax–/– and Lama2–/–Bax+/+ mice were significantly different from each other with P < 0.04 at days 28 and 35 and P < 0.01 at days 42 and 49.