Both humans and snakes that express voltage-gated sodium ion channels (Na V 1.4) with “loss-of-function” mutations in their skeletal muscle recover muscle strength as they age, suggesting there may be a shared mechanism of compensation for reduced channel activity. Congenital myopathies (CMs) in human infants are characterized by neonatal hypotonia and muscle weakness. These symptoms are linked to “loss-of-function” mutations in the SCN4A gene that encodes sodium channels expressed in skeletal muscle (hNa V 1.4). Mutations linked to CMs shift the voltage-dependence of activation in hNa V 1.4 to more depolarized potentials and reduce electrical activity in skeletal muscle fibers. Some populations of garter snakes have evolved resistance to the neurotoxin tetrodotoxin found in their tetrodotoxic prey. These snakes have mutations in tsNa V 1.4 that cause a depolarized shift in activation and, as neonates, slower crawl speed. Both humans and snakes that express channels with “loss-of-function” mutations recover muscle strength as they age. To test possible compensation mechanisms, we modified the Cannon (1993) two-compartment model of skeletal muscle electrical activity (sarcolemma and T-tubule) to simulate the “loss-of-function” properties of snake and human channels. We found a link between depolarized shifts in the voltage-dependence of activation and reduced muscle cell activity in both human and snake models. Shifts in the voltage-dependence of activation altered the voltage threshold for action potentials (APs) in and reduced the electrical activity of model cells. We tested whether increases in hNa V 1.4 expression, proposed to occur during human development, could explain muscle strength recovery in infants with CMs. We found that increasing the conductance of sodium currents (simulating increased expression) increased the probability that both snake and human model cells fired APs at the rapid rates required for skeletal muscle tetanus.
Geffeney et al. (Sun,) studied this question.