Extracellular magnesium and calcium reduce myotonia in ClC-1 inhibited rat muscle

Loss-of-function mutations in the ClC-1 Cl− channel trigger skeletal muscle hyperexcitability in myotonia congenita. For reasons that remain unclear, the severity of the myotonic symptoms can vary markedly even among patients with identical ClC-1 mutations, and may become exacerbated during pregnancy and with diuretic treatment. Since both these conditions are associated with hypomagnesemia and hypocalcemia, we explored whether extracellular Mg2+ and Ca2+ ([Mg2+]o and [Ca2+]o) can affect myotonia. Experimental myotonia was induced in isolated rat muscles by ClC-1 inhibition and effects of [Mg2+]o or [Ca2+]o on myotonic contractions were determined. Both cations dampened myotonia within their physiological concentration ranges. Thus, myotonic contractile activity was 6-fold larger at 0.3 than at 1.2 mM [Mg2+]o and 82-fold larger at 0.3 than at 1.27 mM [Ca2+]o. In intracellular recordings of action potentials, the threshold for action potential excitation was raised by 4-6 mV when [Mg2+]o was elevated from 0.6 to 3 mM, compatible with an increase in the depolarization of the membrane potential necessary to activate the Na+ channels. Supporting this notion, mathematical simulations showed that myotonia went from appearing with normal Cl− channel function to disappearing in the absence of Cl− channel function when Na+ channel activation was depolarized by 6 mV. In conclusion, variation in serum Mg2+ and Ca2+ may contribute to phenotypic variation in myotonia congenita patients.