Onopiuk Marta, Brutkowski Wojciech, Young Christopher, Krasowska Elżbieta, Róg Justyna, Ritso Morten, Wojciechowska Sylwia, Arkle Stephen, Zabłocki Krzysztof, Górecki Dariusz C
Nencki Institute of Experimental Biology, Warsaw, Poland; Departments of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA(1).
School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK; Nencki Institute of Experimental Biology, Warsaw, Poland.
Arch Biochem Biophys. 2015 Mar 1;569:1-9. doi: 10.1016/j.abb.2015.01.025. Epub 2015 Feb 4.
Sarcolemma damage and activation of various calcium channels are implicated in altered Ca(2+) homeostasis in muscle fibres of both Duchenne muscular dystrophy (DMD) sufferers and in the mdx mouse model of DMD. Previously we have demonstrated that also in mdx myoblasts extracellular nucleotides trigger elevated cytoplasmic Ca(2+) concentrations due to alterations of both ionotropic and metabotropic purinergic receptors. Here we extend these findings to show that the mdx mutation is associated with enhanced store-operated calcium entry (SOCE). Substantially increased rate of SOCE in mdx myoblasts in comparison to that in control cells correlated with significantly elevated STIM1 protein levels. These results reveal that mutation in the dystrophin-encoding Dmd gene may significantly impact cellular calcium response to metabotropic stimulation involving depletion of the intracellular calcium stores followed by activation of the store-operated calcium entry, as early as in undifferentiated myoblasts. These data are in agreement with the increasing number of reports showing that the dystrophic pathology resulting from dystrophin mutations may be developmentally regulated. Moreover, our results showing that aberrant responses to extracellular stimuli may contribute to DMD pathogenesis suggest that treatments inhibiting such responses might alter progression of this lethal disease.
杜氏肌营养不良症（DMD）患者以及DMD的mdx小鼠模型的肌纤维中，肌膜损伤和各种钙通道的激活与Ca(2+)稳态改变有关。此前我们已经证明，在mdx成肌细胞中，由于离子型和代谢型嘌呤能受体的改变，细胞外核苷酸也会引发细胞质Ca(2+)浓度升高。在此，我们扩展这些发现，以表明mdx突变与增强的储存-操作性钙内流（SOCE）相关。与对照细胞相比，mdx成肌细胞中SOCE的速率显著增加，这与STIM1蛋白水平显著升高相关。这些结果表明，早在未分化的成肌细胞中，编码抗肌萎缩蛋白的Dmd基因突变可能会显著影响细胞对代谢型刺激的钙反应，这种刺激涉及细胞内钙库的耗尽，随后是储存-操作性钙内流的激活。这些数据与越来越多的报告一致，这些报告表明由抗肌萎缩蛋白突变引起的营养不良病理可能受发育调控。此外，我们的结果表明对细胞外刺激的异常反应可能导致DMD发病机制，这表明抑制这种反应的治疗可能会改变这种致命疾病的进展。
