Muscle-specific BCL2 expression ameliorates muscle disease in laminin {alpha}2-deficient, but not in dystrophin-deficient, mice.
To examine the role of apoptosis in neuromuscular disease progression, we have determined whether pathogenesis in dystrophin-deficient (mdx) and laminin alpha2-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 alpha2 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.
Dominov
Janice A
JA
Boston Biomedical Research Institute, 64 Grove Street, Watertown, MA 02472, USA. dominov@bbri.org
Kravetz
Amanda J
AJ
Ardelt
Magdalena
M
Kostek
Christine A
CA
Beermann
Mary Lou
ML
Miller
Jeffrey B
JB
D000818:Animals; D016189:Dystrophin / Q000172:deficiency*; D006801:Humans; D007797:Laminin / Q000172:deficiency*; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D009132:Muscles / Q000378:metabolism*; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics*
D016189:Dystrophin; D007797:Laminin; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C102645:laminin alpha 2; C052617:Bcl2 protein, mouse