Proposed Mechanism for Post‐Exercise Weakness in Hypokalemic Periodic Paralysis

Hypokalemic periodic paralysis (HypoKPP) is a dominantly inherited channelopathy of skeletal muscle in which recurrent episodes of severe weakness are often provoked by environmental triggers such as carbohydrate ingestion, K + loss, or exercise. Remarkably, the mutations that cause HypoKPP occur almost exclusively at arginine residues in the S4 voltage sensor domains of the L‐type Ca channel (Ca V 1.1) or the voltage‐gated sodium channel (Na V 1.4). These R/X mutations of S4 produce an anomalous conduction pathway that is permissive (open) at hyperpolarized potentials. This so‐called gating pore leakage current renders the muscle fiber susceptible to anomalous depolarization of Vrest in low K + (e.g. 2 to 3 mM). Depolarized fibers are refractory to the generation of action potentials, resulting in loss of force. While this low K + induced basis for episodic weakness is well established, the mechanism by which weakness occurs within minutes of resting after strenuous exercise is completely unknown. We tested the hypothesis that acidosis is a trigger for exercise‐induced attacks of weakness in HypoKPP. This notion was explored in our previously developed knock‐in mutant mouse models of HypoKPP (NaV1.4‐R669H and CaV1.1‐R528H). The soleus muscle was mounted in an HCO 3 buffered tissue bath and maximal isometric force was measured during tetanic stimulation (100 Hz, 40 pulses). Acidosis was imposed by bath exchange with a solution equilibrated to 25% CO 2 (pH 6.8), compared to baseline 5% (pH 7.4). Acidosis was well tolerated for WT and HypoKPP muscle during a 20 min exposure to 25% CO 2 . Upon return to 5% CO 2 , however, there was a marked transient decrease in force for HypoKPP muscle but not for WT. Myoplasmic pH homeostasis in response to the 25% CO 2 challenge was indistinguishable for WT and HypoKPP muscle, as measured with BCECF. We propose the transient weakness is caused by a pH‐dependent rise of myoplasmic Cl. Acidosis reduces the ClC‐1 conductance (G Cl ), thereby limiting Cl efflux, while influx via the NKCC cotransporter produces a slow rise of myoplasmic Cl. A rapid correction of pH quickly increases G Cl which depolarizes the fiber because of the shift of E Cl . In support of this hypothesis, inhibition of NKCC with bumetanide completely prevents the post‐acidosis loss of force. Model simulations show myoplasmic Cl accumulation and susceptibility to depolarization are greater for HypoKPP muscle than WT due to the gating pore current. We propose the post‐exercise weakness in HypoKPP muscle is caused by a shift of Cl into muscle while G Cl is low during acidosis, followed by depolarization if G Cl recovers quickly. A slower recovery from acidosis my allow the Cl gradient to return to baseline before a full recovery of G Cl , thereby reducing the risk of paralysis as patients have reported with warm‐down after exercise. Support or Funding Information Supported by the National Institutes of Arthritis, Musculoskeletal, and Skin Diseases of the NIH (Grants AR42703 and AR063182).