Persistent Inward Currents Play a Role in Muscle Dysfunction Seen inMyotonia Congenita

Myotonia congenita is a rare skeletal muscle channelopathy caused by a reduced chloride channel (ClC-1) current, which results in debilitating muscle hyperexcitability, prolonged contractions, and transient episodes of weakness. The excitatory events that trigger myotonic action potentials in the absence of stabilizing ClC-1 current are not fully understood. My in vitro intracellular recordings from a mouse homozygous knockout of ClC-1 revealed a slow after-depolarization (AfD) that triggers myotonic action potentials. The AfD is well-explained by a tetrododoxin-sensitive and voltage-dependent Na+ persistent inward current (NaPIC). Notably, this NaPIC undergoes slow inactivation over seconds, thus providing the first mechanistic explanation for the end of myotonic runs. Highlighting the significance of this mechanism, we show that ranolazine and elevated serum divalent cations eliminate myotonia by inhibiting AfD and NaPIC. The electrophysiological events responsible for the transient weakness are not well understood either. My in vitro intracellular recordings revealed a novel behavior, in which the muscle is functionally inexcitable for seconds to minutes. This hanging behavior, as I refer to it, is likely to be responsible for periods of weakness described by patients and is explained by another persistent inward current. Partial pharmacological block of this other PIC decreases the hanging behavior in myotonic muscle.This work significantly changes our understanding of the mechanisms underlying myotonia and transient weakness seen in myotonia congenita and reveals a novel and highly effective therapeutic target.