Reduced Extracellular [Ca2+] Increases the Sensitivity of Mouse EDL and Soleus to the K+‐Induced Force Depression: Implication for the Increased Sensitivity of Hyperkalemic Periodic Paralysis Muscles to Calcium Levels

Abstract

Hyperkalemic periodic paralysis (HyperKPP) is a disease of altered skeletal muscle excitability due to missense mutations in the skeletal muscle Na+ channel (NaV1.4). It is primarily characterized by myotonic discharges between and during periods of paralysis that mainly affect limb muscles. The paralysis is induced by large membrane depolarizations associated with the increase in Na+ influx and accumulation of extracellular [K+] during the myogenic discharge. Patients can be alleviated of their paralysis by taking salbutamol and/or ingesting Ca2+. While salbutamol mechanism of action involves an improved resting membrane potential and an increase in Ca2+ release, the effect of Ca2+ is not well understood except that a large increase in extracellular [Ca2+]e ([Ca2+]e) reduces the K+‐induced force depression. The objective of this study was therefore to test the hypothesis that a reduced [Ca2+]e increases the extent of the K+‐induced force depression and reduces the salbutamol‐induced increase in force at elevated [K+]e. A decrease in [Ca2+]e from 2.4 mM to 0.3 mM had no effect on the tetanic force of both wild type mouse EDL and soleus when [K+]e was at the normal 4.7 mM. However, it significantly shifted the tetanic force‐[K+]e relationship to lower [K+]e. At 2.4 mM Ca2+ and 4.7 mM K+, HyperKPP EDL and soleus generated as much tetanic force as their wild type counterpart. However, decreases in [Ca2+]e to 1.3 and 0.3 mM significantly reduced tetanic force at 4.7 mM and caused large and significant shift of the tetanic force‐[K+]e relationship to lower [K+]e. Lowering [Ca2+]e did not affect the efficacy of salbutamol to increase tetanic force when it had been depressed by an increase in [K+]e in either wild type or HyperKPP muscles. Considering that at 4.7 mM K+, several HyperKPP EDL and soleus fibers are depolarized and that the effect of lower [Ca2+]e occurred when the cell membrane is depolarized by increases in [K+]e, it is suggested that the increased sensitivity of HyperKPP muscles to Ca2+ is primarily because of a large number of fibers with depolarized cell membrane even when [K+]e is at its normal value of 4.7 mM.Support or Funding InformationThis study was supported by the Canadian Institute of Health Research (CIHR)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.