The mechanisms responsible for the onset and progressive worsening of episodic muscle stiffness and weakness in hyperkalemic periodic paralysis (Hyper KPP) are not fully understood. Using a knock-in Hyper KPP mouse model harboring the M1592V NaV1.4 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 Hyper KPP 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. Hyper KPP 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. NaV1.4 channel protein content reached adult level by 3 weeks postnatal in both wild type and Hyper KPP and apparent symptoms did not worsen after the first month of age suggesting (i) that the phenotypic behavior of M1592V Hyper KPP muscles results from defective function of mutant NaV1.4 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 Hyper KPP symptoms during adolescence are a function of NaV1.4 channel content. [ABSTRACT FROM AUTHOR]