UCLA

The precise control of skeletal muscle excitation, contraction, and relaxation relies upon a highly choreographed sequence of ionic currents in the sarcolemmal membrane. Mutations of ion channels can lead to deleterious changes of ionic currents that impair muscle fiber excitability and thereby cause either weakness or involuntary after-contractions. The work presented here aims to define the functional consequences for newly identified disease mutations in a sodium channel and to establish the mechanism by which the partial loss of a potassium conductance creates susceptibility to episodic attacks of weakness.

The majority of this work focuses on Andersen-Tawil syndrome, a form of periodic paralysis caused by loss-of-function mutations of the inward rectifying potassium channel Kir2.1. While a genetic basis was established for the disease, it was unknown how this defect creates susceptibility to episodes weakness, or whether as in other forms of periodic paralysis, the attacks are exacerbated by low or high potassium. To investigate this, we generated two different mouse models of ATS, one genetic and the other pharmacologic, that enabled us to explore the mechanistic relationship between the loss of a potassium conductance and the functional deficits in muscle excitation and contraction. We found that loss of muscle force was consistently induced by a high-K challenge, whereas only in the setting of a severely reduced the inward rectifier current (e.g. 6% remaining) did the muscle also exhibit weakness in a low-K challenge. Simulations of a model fiber provided insights on this divergent K-dependence for eliciting weakness and also identified approaches for manipulating conductances, transporters, or pumps to reduce the likelihood of an episode of paralysis. We tested a variety of agents and found that KATP channel openers may provide a means for pharmacologic intervention.

The remainder of the work characterizes two newly identified mutations in the voltage-gated sodium channel (NaV1.4). The first is a novel loss-of-function mutation found in recessive congenital myopathy plus fluctuating weakness. The second study identified gain-of-function changes for a NaV1.4 mutation associated with an unusually early onset of myotonia with congenital anomalies, and defined a new syndrome, myotonic myopathy with secondary joint and bone anomalies.