Plateau potentials contribute to myotonia in mouse models of myotonia congenita

Abstract

It has long been accepted that myotonia (muscle stiffness) in patients with muscle channelopathies is due to myotonic discharges (involuntary firing of action potentials). In a previous study, we identified a novel phenomenon in myotonic muscle: development of plateau potentials, transient depolarizations to near -35 mV lasting for seconds to minutes. In the current study we examined whether plateau potentials contribute to myotonia. A recessive genetic model (ClC^adr mice) with complete loss of muscle chloride channel (ClC-1) function was used to model severe myotonia congenita with complete loss of ClC-1 function and a pharmacologic model using anthracene-9-carboxylic acid (9 AC) was used to model milder myotonia congenita with incomplete loss of ClC-1 function. Simultaneous measurements of action potentials and myoplasmic Ca²⁺ from individual muscle fibers were compared to recordings of whole muscle force generation. In ClC^adr muscle both myotonia and plateau potentials lasted 10s of seconds to minutes. During plateau potentials lasting 1-2 min, there was a gradual transition from high to low intracellular Ca²⁺, suggesting a transition in individual fibers from myotonia to flaccid paralysis in severe myotonia congenita. In 9 AC-treated muscles, both myotonia and plateau potentials lasted only a few seconds and Ca²⁺ remained elevated during the plateau potentials, suggesting plateau potentials contribute to myotonia without causing weakness. We propose, that in myotonic muscle, there is a novel state in which there is contraction in the absence of action potentials. This discovery provides a mechanism to explain reports of patients with myotonia who suffer from electrically silent muscle contraction lasting minutes.

Keywords: Action potential; Excitability; Muscle; Myotonia; Stiffness; Weakness.