Physiological basis for muscle stiffness and weakness in a knock‐in M1592V mouse model of hyperkalemic periodic paralysis. Issue 12 (23rd December 2015)

• Record Type: Journal Article
• Authors: Khogali, Shiemaa; Lucas, Brooke; Ammar, Tarek; Dejong, Danica; Barbalinardo, Michael; Hayward, Lawrence J.; Renaud, Jean‐Marc
• Is Part Of: Physiological reports. Volume 3:Issue 12(2015:Dec.)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2015-12-23
• Subjects: Calcium -- EMG -- potassium -- tetanic force; Physiology -- Periodicals; 571
• DOI: 10.14814/phy2.12656
• Languages: English
• ISSNs: 2051-817X

Abstract

Abstract: The mechanisms responsible for the onset and progressive worsening of episodic muscle stiffness and weakness in hyperkalemic periodic paralysis (HyperKPP) are not fully understood. Using a knock‐in HyperKPP mouse model harboring the M1592V NaV 1.4 channel mutant, we interrogated changes in physiological defects during the first year, including tetrodotoxin‐sensitive Na + influx, hindlimb electromyographic (EMG) activity and immobility, muscle weakness induced by elevated [K + ]e, myofiber‐type composition, and myofiber damage. In situ EMG activity was greater in HyperKPP than wild‐type gastrocnemius, whereas spontaneous muscle contractions were observed in vitro. We suggest that both the greater EMG activity and spontaneous contractions are related to periods of hyperexcitability during which fibers generate action potentials by themselves in the absence of any stimulation and that these periods are the cause of the muscle stiffness reported by patients. HyperKPP muscles had a greater sensitivity to the K + ‐induced force depression than wild‐type muscles. So, an increased interstitial K + concentration locally near subsets of myofibers as a result of the hyperexcitability likely produced partial loss of force rather than complete paralysis. NaV 1.4 channel protein content reached adult level by 3 weeks postnatal in both wild type and HyperKPP and apparent symptoms did not worsen after the first month of age suggesting (i) that the phenotypic behavior of M1592V HyperKPP muscles results from defective function of mutant NaV 1.4 channels rather than other changes in protein expression after the first month and (ii) that the lag in onset during the first decade and the progression of human HyperKPP symptoms during adolescence are a function of NaV 1.4 channel content. Abstract : This study further characterized the mechanisms that cause muscle stiffness and weakness in Hyperkalemic Periodic Paralysis (HyperKPP). Muscle stiffness is caused by an increased membrane hyperexcitability as action potentials are generated in the absence of motorneuron stimulation in random as opposed to myotonic discharges as clinically defined. Muscle weakness is caused by localized increases in extracellular potassium concentration that cause membrane hypoexcitability in a few fibers at a time.