Targeted inhibition of Ca2+/calmodulin signaling exacerbates the dystrophic phenotype in mdx mouse muscle
Targeted inhibition of Ca2+/calmodulin signaling exacerbates the dystrophic phenotype in mdx mouse muscle
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DOI：
10.1093/hmg/ddl065
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发表时间：
2006-05-01
影响因子：
3.5
通讯作者：
Jasmin, BJ
中科院分区：
文献类型：
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作者：
Chakkalakal, JV;Michel, SA;Jasmin, BJ
在这项研究中，我们将mdx小鼠与表达钙调蛋白（CaM）小肽抑制剂的转基因小鼠杂交，称为CaM结合蛋白（CaMBP），由慢纤维特异性肌钙蛋白I慢启动子驱动。这一策略使我们能够确定干扰Ca2+/ cam信号对肌营养不良蛋白缺乏的慢肌纤维的影响。与Ca2+/ cam调节酶钙调磷酸酶和Ca2+/ cam依赖性激酶的损伤一致，mdx/CaMBP小鼠的慢纤维中活化t细胞c1和心肌细胞增强因子2C的核因子积累减少。我们还检测到mdx/CaMBP小鼠慢纤维富比目鱼肌中过氧化物酶体增殖因子γ共激活因子1 α和ga结合蛋白α mrna水平的显著降低。同时，我们观察到mdx/CaMBP比目鱼肌中肌球蛋白重链I mRNA的表达显著降低。这与纤维型向更快的表型转移有关。mdx/CaMBP慢肌纤维检测显示a -肌营养蛋白显著减少，a -肌营养蛋白是一种治疗相关蛋白，可以补偿骨骼肌中肌营养不良蛋白的缺乏。根据a -营养蛋白水平的降低，我们注意到mdx/CaMBP慢纤维的营养不良表型明显加剧，这是几个病理指标的例证。这些结果坚定地确立了Ca2+/ cam信号是调节肌肉中A-utrophin表达的关键。此外，这项研究说明了使用Ca2+/ cam信号靶点作为治疗杜氏肌营养不良症（DMD）的策略的治疗潜力。最后，我们的研究结果进一步支持了这样一个概念，即旨在促进肌肉中缓慢氧化肌纤维程序的策略可能有效地改变DMD的无情进展。
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 gamma co-activator 1 alpha 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 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.