Human Molecular Genetics Advance Access originally published online on March 9, 2005
Human Molecular Genetics 2005 14(8):1029-1040; doi:10.1093/hmg/ddi095
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Muscle-specific BCL2 expression ameliorates muscle disease in laminin 
2-deficient, but not in dystrophin-deficient, mice
1Boston Biomedical Research Institute, 64 Grove Street, Watertown, MA 02472, USA and 2Department of Neurology, Harvard Medical School, Boston, MA 02115, USA
* To whom correspondence should be addressed. Tel: +1 6176587739; Fax: +1 6179721761; Email: dominov{at}bbri.org
Received December 18, 2004; Revised February 17, 2005; Accepted February 28, 2005
To examine the role of apoptosis in neuromuscular disease progression, we have determined whether pathogenesis in dystrophin-deficient (mdx) and laminin 
2-deficient (Lama2-null) mice is ameliorated by overexpression of the anti-apoptosis protein BCL2 in diseased muscles. The mdx mice are a model for the human disease, Duchenne muscular dystrophy (DMD), and the Lama2-null mice are a model for human congenital muscular dystrophy type 1A (MDC1A). For these studies, we generated transgenic mice that overexpressed human BCL2 under control of muscle-specific MyoD or MRF4 promoter fragments. We then used cross-breeding to introduce the transgenes into diseased mdx or Lama2-null mice. In mdx mice, we found that overexpression of BCL2 failed to produce any significant differences in muscle pathology. In contrast, in the Lama2-null mice, we found that muscle-specific expression of BCL2 led to a several-fold increase in lifespan and an increased growth rate. Thus, BCL2-mediated apoptosis appears to play a significant role in pathogenesis of laminin 2 deficiency, but not of dystrophin deficiency, suggesting that therapies designed to ameliorate disease by inhibition of apoptosis are more likely to succeed in MDC1A than in DMD.
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