Human Molecular Genetics Advance Access originally published online on March 21, 2006
Human Molecular Genetics 2006 15(9):1423-1435; doi:10.1093/hmg/ddl065
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Targeted inhibition of Ca2+/calmodulin signaling exacerbates the dystrophic phenotype in mdx mouse muscle
1Department of Cellular and Molecular Medicine, Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ont., Canada K1H 8M5, 2Departments of Chemistry and Biochemistry and Exercise Science, Centre for Structural and Functional Genomics, Concordia University, The Richard J. Renaud Science Complex, Montreal, Que., Canada H4B 1R6, 3Research Pharmacology, Pfizer Global Research and Development, San Diego, CA, USA and 4Ottawa Health Research Institute, Molecular Medicine Program, Ottawa Hospital, General Campus, Ottawa, Ont., Canada K1H 8L6
* To whom correspondence should be addressed at: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ont., Canada K1H 8M5. Tel: +1 6135625800 ext: 8383; Fax: +1 6135625636; Email: jasmin{at}uottawa.ca
Received January 12, 2006; Accepted March 14, 2006
In this study, we crossbred mdx mice with transgenic mice expressing a small peptide inhibitor for calmodulin (CaM), known as the CaM-binding protein (CaMBP), driven by the slow fiber-specific troponin I slow promoter. This strategy allowed us to determine the impact of interfering with Ca2+/CaM-based signaling in dystrophin-deficient slow myofibers. Consistent with impairments in the Ca2+/CaM-regulated enzymes calcineurin and Ca2+/CaM-dependent kinase, the nuclear accumulation of nuclear factor of activated T-cell c1 and myocyte enhancer factor 2C was reduced in slow fibers from mdx/CaMBP mice. We also detected significant reductions in the levels of peroxisome proliferator 
co-activator 1
and GA-binding protein mRNAs in slow fiber-rich soleus muscles of mdx/CaMBP mice. In parallel, we observed significantly lower expression of myosin heavy chain I mRNA in mdx/CaMBP soleus muscles. This correlated with fiber-type shifts towards a faster phenotype. Examination of mdx/CaMBP slow muscle fibers revealed significant reductions in A-utrophin, a therapeutically relevant protein that can compensate for the lack of dystrophin in skeletal muscle. In accordance with lower levels of A-utrophin, we noted a clear exacerbation of the dystrophic phenotype in mdx/CaMBP slow fibers as exemplified by several pathological indices. These results firmly establish Ca2+/CaM-based signaling as key to regulating expression of A-utrophin in muscle. Furthermore, this study illustrates the therapeutic potential of using targets of Ca2+/CaM-based signaling as a strategy for treating Duchenne muscular dystrophy (DMD). Finally, our results further support the concept that strategies aimed at promoting the slow oxidative myofiber program in muscle may be effective in altering the relentless progression of DMD.
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