Diaphragm of Hyperkalemic Periodic Paralysis Mouse Has No Contractility Abnormality Compared to the Robust Abnormalities in EDL and Soleus

Abstract

Hyperkalemic periodic paralysis (HyperKPP) is an autosomal dominant disease that is caused by mutations in the SCN4A gene that encodes for the Nav1.4 channel, the skeletal muscle isoform of Na+channels. HyperpKPP patients suffer from both myotonia and limb paralysis. The myotonia is the result of large membrane depolarization due to large Na+ influx through defective NaV1.4 channels, while the paralysis is caused by increases in extracellular [K+] [[K+]e). However; even though diaphragm also expresses Nav1.4 channels, HyperKPP patients rarely suffer from respiratory distress, as expected with any paralysis. Despite the fact that Na+ influxes through mutated NaV1.4 channels in diaphragm, soleus and EDL muscles from a HyperKPP mouse model are all significantly greater than in their WT counterparts, the HyperKPP diaphragm is the only muscles being spared from the K+‐induced paralysis. The lack of paralysis in diaphragm is not related to any significant increases in Na+ K+ ATPase α‐1 and α‐2 protein content, which actually only increased in HyperKPP EDL. Measurements of resting membrane potential (resting Em) and force demonstrated that the lower force generation in HyperKPP EDL and soleus compared to wild type muscles at different [K+]e was in part related to greater membrane depolarization when [K+]e was increased. However, for a given [K+]e or resting EM, HyperKPP diaphragm generated more force than WT diaphragm. It is proposed that another membrane component spares diaphragm from HyperKPP symptoms, possibly the Na+Ca2+ exchanger which can increase [Ca2+]i during contraction when [Na+]i is elevated as it does in cardiac muscle.