Targeted inhibition of Ca2+ /calmodulin signaling exacerbates the dystrophic phenotype in mdx mouse muscle.
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 Ca(2+)/CaM-based signaling in dystrophin-deficient slow myofibers. Consistent with impairments in the Ca(2+)/CaM-regulated enzymes calcineurin and Ca(2+)/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 gamma co-activator 1alpha and GA-binding protein alpha 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 Ca(2+)/CaM-based signaling as key to regulating expression of A-utrophin in muscle. Furthermore, this study illustrates the therapeutic potential of using targets of Ca(2+)/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.
Chakkalakal
Joe V
JV
Department of Cellular and Molecular Medicine, Centre for Neuromuscular Diseases, Faculty of Medicine, University of Ottawa, Ottawa, Ont., Canada K1H 8M5.
Michel
Stephanie A
SA
Chin
Eva R
ER
Michel
Robin N
RN
Jasmin
Bernard J
BJ
D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000502:physiology; D020013:Calcium Signaling / Q000235:genetics*; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000502:physiology; D002148:Calmodulin-Binding Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D018450:Disease Progression; D005260:Female; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000473:pathology* / Q000628:therapy
D002147:Calmodulin; D002148:Calmodulin-Binding Proteins; D002118:Calcium