Contractile abnormalities of mouse muscles expressing hyperkalemic periodic paralysis mutant NaV1.4 channels do not correlate with Na super(+) influx or channel content

Hyperkalemic periodic paralysis (HyperKPP) is characterized by myotonic discharges that occur between episodic attacks of paralysis. Individuals with HyperKPP rarely suffer respiratory distress even though diaphragm muscle expresses the same defective Na super(+) channel isoform (NaV1.4) that causes symptoms in limb muscles. We tested the hypothesis that the extent of the HyperKPP phenotype (low force generation and shift toward oxidative type I and IIA fibers) in muscle is a function of 1) the NaV1.4 channel content and 2) the Na super(+) influx through the defective channels [i.e., the tetrodotoxin (TTX)-sensitive Na super(+) influx]. We measured NaV1.4 channel protein content, TTX-sensitive Na super(+) influx, force generation, and myosin isoform expression in four muscles from knock-in mice expressing a NaV1.4 isoform corresponding to the human M1592V mutant. The HyperKPP flexor digitorum brevis muscle showed no contractile abnormalities, which correlated well with its low NaV1.4 protein content and by far the lowest TTX-sensitive Na super(+) influx. In contrast, diaphragm muscle expressing the HyperKPP mutant contained high levels of NaV1.4 protein and exhibited a TTX-sensitive Na super(+) influx that was 22% higher compared with affected extensor digitorum longus (EDL) and soleus muscles. Surprisingly, despite this high burden of Na super(+) influx, the contractility phenotype was very mild in mutant diaphragm compared with the robust abnormalities observed in EDL and soleus. This study provides evidence that HyperKPP phenotype does not depend solely on the NaV1.4 content or Na influx and that the diaphragm does not depend solely on Na super(+)-K super(+) pumps to ameliorate the phenotype.