OBJECTIVES: Permanent weakness is a feature of several muscle channelopathies in older age but it is usually thought to be irreversible and thus left untreated. We studied the pathogenesis of the permanent weakness and possibilities of therapy. METHODS: Membrane potentials and twitch force were measured excised patient and control muscle fiber strips. In-vivo 23Na magnetic resonance imaging (MRI), fat-suppressed 1H-MRI, and force assessment were performed to determine intramuscular Na+ load, edema, and muscle strength in patients under different conditions. RESULTS: Of the 36 patients, 25 presented with continuous muscle weakness of varying degrees, up to wheelchair-dependence. The weakness was associated with intracellular Na+ overload and oedema. Weakness, intracellular Na+ overload and oedema were increased by cooling and glucose/insulin; and almost completely normalized by 4 weeks of treatment with the carbonic anhydrase inhibitor acetazolamide or the new aldosterone antagonist eplerenone. In vitro, the continuous weakness correlated to membrane depolarization. Acetazolamide repolarized the membrane and restored force. CONCLUSIONS: Membrane depolarization associated with intracellular Na+ and water overload causes muscle weakness. Acetazolamide has direct and beneficial effects on the muscle and can markedly improve continuous weakness. REFERENCE: Jurkat-Rott, K., Weber, M.A., Fauler, M., Guo, X.H., Holzherr, B.D., Paczulla, A., Nordsborg, N., Joechle, W. & Lehmann-Horn, F. 2009. Proc Natl Acad Sci 106:4036-41.