Eplerenone repolarizes muscle membrane through Na,K-ATPase activation by Tyr10 dephosphorylation.
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.
Division of Neurophysiology, Ulm University, Germany.
Simon
S
Breitenbach
Division of Neurophysiology, Ulm University, Germany.
Frank
F
Lehmann-Horn
Department of Neurosurgery, Ulm University, Germany.
Karin
K
Jurkat-Rott
D000818:Animals; D002460:Cell Line; D003964:Diaphragm / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000077545:Eplerenone; D008564:Membrane Potentials / Q000187:drug effects*; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D004791:Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D013148:Spironolactone; D010042:Ouabain; D000077545:Eplerenone; D051057:Proto-Oncogene Proteins c-akt; C499075:Atp1a1 protein, rat; C497344:Atp1a1 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase
ATPase; Duchenne muscular dystrophy; eplerenone