Targeted single point mutation of NaV1.4 in mouse increases sodium influx and potassium‐induced force depression in EDL and soleus muscle

Abstract

The single point mutation M1592V on the human skeletal muscle sodium channel, NaV1.4, causes Hyperkalemic Periodic Paralysis (HyperKPP). HyperKPP is associated with greater sodium influx and sensitivity to the potassium depressing effect on force. The objective of this study was to determine if introducing a missense substitution corresponding to a human familial HyperKPP mutation (Met1592Val) into the mouse gene (mice(+/M1592V)) encoding the skeletal muscle voltage‐gated Na+ channel NaV1.4 also results in greater sodium flux and potassium sensitivity. EDL and soleus muscles were exposed to either 4.7 mM (control) or 9–10 mM K+ while measuring either 22Na+ uptake or peak tetanic force. 22Na+ uptake was 3‐times greater in EDL and soleus muscles of mice(+/M1592V) when compared to the uptake in wild type muscles. The drop in peak tetanic force at 9–10 mM was much greater in EDL and soleus muscles of mice(+/M1592V) than in wild type muscles. Furthermore, adding 1–2 nM TTX, to partially block sodium channels, caused a decrease in peak tetanic force in wild type muscles but produced an increase in force in EDL and soleus muscles of mice(+/M1592V). However, the peak tetanic force of muscle(+/M1592V) in the presence of TTX was still less than that observed in wild type muscles. We conclude that the introduction of the M1592V mutation in the mouse genome increases sodium influx and the K+ sensitivity of skeletal muscle as observed in human suffering of HyperKPP. However, partially blocking Na+ channels with TTX failed to return the force back to the level observed in wild type muscles, which suggests that an increased intracellular sodium also contributes to the reduced force.