Breitenbach Simon, Lehmann-Horn Frank, Jurkat-Rott Karin
Division of Neurophysiology, Ulm University, Germany.
Department of Neurosurgery, Ulm University, Germany.
Acta Myol. 2016 Oct;35(2):86-89.
Eplerenone, an aldosterone antagonist, repolarizes muscle membrane in-vitro and increases strength in-vivo in channelopathies. In Duchenne dystrophy, it is administered for cardiomyopathy. We studied its mechanism of action on skeletal muscle to test its suitability for increasing strength in Duchenne dystrophy. Using membrane potential measurements, quantitative PCR, ELISA, and Western blots, we examined the effects of eplerenone on skeletal muscle Na,K-ATPase. The repolarizing effect of eplerenone in muscle fibres was counteracted by oubain, an ATPase blocker. In our experiment, ATPA1A mRNA and total ATPase protein were not elevated. Instead, Tyr10 of the α1 subunit was dephosphorylated which would agree with ATPase activation. Dephosporylation of the coupled Akt kinase corroborated our findings. We conclude that eplerenone repolarizes muscle membrane by Na,K-ATPase activation by dephosphorylation at Tyr10. Since ATPase protein is known to be compensatorily increased in Duchenne patients without activity change, eplerenone treatment may be beneficial.
依普利酮是一种醛固酮拮抗剂，在体外可使肌膜复极化，并在体内增强通道病患者的肌力。在杜氏肌营养不良症中，它被用于治疗心肌病。我们研究了其对骨骼肌的作用机制，以测试其是否适合用于增强杜氏肌营养不良症患者的肌力。通过膜电位测量、定量聚合酶链反应、酶联免疫吸附测定和蛋白质免疫印迹法，我们检测了依普利酮对骨骼肌钠钾ATP酶的影响。依普利酮在肌纤维中的复极化作用被ATP酶阻滞剂哇巴因抵消。在我们的实验中，ATP1A1信使核糖核酸和总ATP酶蛋白并未升高。相反，α1亚基的酪氨酸10被去磷酸化，这与ATP酶激活一致。偶联的Akt激酶的去磷酸化证实了我们的发现。我们得出结论，依普利酮通过使酪氨酸10去磷酸化激活钠钾ATP酶，从而使肌膜复极化。由于已知杜氏病患者的ATP酶蛋白会代偿性增加而活性不变，依普利酮治疗可能有益。
