scholarly journals Recovery from acidosis is a robust trigger for loss of force in murine hypokalemic periodic paralysis

2019 ◽  
Vol 151 (4) ◽  
pp. 555-566 ◽  
Author(s):  
Wentao Mi ◽  
Fenfen Wu ◽  
Marbella Quinonez ◽  
Marino DiFranco ◽  
Stephen C. Cannon
Keyword(s):  
Mouse Models ◽  
Muscle Force ◽  
Mutant Mouse ◽  
Prolonged Exposure ◽  
Periodic Paralysis ◽  
Resting Potential ◽  
Hypokalemic Periodic Paralysis ◽  
Vigorous Exercise ◽  
Exercise Induced ◽  
Cl Conductance

Periodic paralysis is an ion channelopathy of skeletal muscle in which recurrent episodes of weakness or paralysis are caused by sustained depolarization of the resting potential and thus reduction of fiber excitability. Episodes are often triggered by environmental stresses, such as changes in extracellular K+, cooling, or exercise. Rest after vigorous exercise is the most common trigger for weakness in periodic paralysis, but the mechanism is unknown. Here, we use knock-in mutant mouse models of hypokalemic periodic paralysis (HypoKPP; NaV1.4-R669H or CaV1.1-R528H) and hyperkalemic periodic paralysis (HyperKPP; NaV1.4-M1592V) to investigate whether the coupling between pH and susceptibility to loss of muscle force is a possible contributor to exercise-induced weakness. In both mouse models, acidosis (pH 6.7 in 25% CO2) is mildly protective, but a return to pH 7.4 (5% CO2) unexpectedly elicits a robust loss of force in HypoKPP but not HyperKPP muscle. Prolonged exposure to low pH (tens of minutes) is required to cause susceptibility to post-acidosis loss of force, and the force decrement can be prevented by maneuvers that impede Cl− entry. Based on these data, we propose a mechanism for post-acidosis loss of force wherein the reduced Cl− conductance in acidosis leads to a slow accumulation of myoplasmic Cl−. A rapid recovery of both pH and Cl− conductance, in the context of increased [Cl]in/[Cl]out, favors the anomalously depolarized state of the bistable resting potential in HypoKPP muscle, which reduces fiber excitability. This mechanism is consistent with the delayed onset of exercise-induced weakness that occurs with rest after vigorous activity.

scholarly journals The Role of Action Potential Waveform in Failure of Excitation Contraction Coupling

2021 ◽  
Author(s):  
Xueyong Wang ◽  
Murad Nawaz ◽  
Steve RA Burke ◽  
Roger Bannister ◽  
Brent D Foy ◽  
...  
Keyword(s):  
Close Correlation ◽  
Periodic Paralysis ◽  
Resting Potential ◽  
Vigorous Exercise ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Simultaneous Imaging ◽  
Sudden Failure ◽  
Action Potential Waveform ◽  
Potential Failure

Excitation contraction coupling (ECC) is the process by which electrical excitation of muscle is converted into force generation. Depolarization of skeletal muscle resting potential contributes to failure of ECC in diseases such as periodic paralysis, ICU acquired weakness and possibly fatigue of muscle during vigorous exercise. When extracellular K+ is raised to depolarize the resting potential, failure of ECC occurs suddenly, over a range of several mV of resting potential. While some studies have hypothesized the sudden failure of ECC is due to all-or-none failure of excitation, other studies suggest failure of excitation is graded. Intracellular recordings of action potentials (APs) in individual fibers during depolarization revealed that APs do not fail in an all-or-none manner. Simultaneous imaging of Ca2+ transients during depolarization revealed failure over a narrow range of resting potentials. An AP property that closely correlated with the sudden failure of the Ca2+ transient was the integral of AP voltage with respect to time. We hypothesize the close correlation is due to the combined dependence on time and voltage of Ca2+ release from the sarcoplasmic reticulum. The quantitative relationships established between resting potential, APs and Ca2+ transients provide the foundation for future studies of depolarization-induced failure of ECC in diseases such as periodic paralysis.

scholarly journals CaV1.1 defects in hypokalemic periodic paralysis and harnessing multiple approaches for therapeutic intervention

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Fenfen Wu ◽  
Marbella Quiñonez ◽  
Marino Difranco ◽  
Stephen Cannon
Keyword(s):  
Late Onset ◽  
Periodic Paralysis ◽  
Resting Potential ◽  
K Channel ◽  
Hypokalemic Periodic Paralysis ◽  
Leakage Currents ◽  
Expression Studies ◽  
Voltage Dependent ◽  
Low K

The recurrent attacks of weakness in hypokalemic periodic paralysis (HypoPP) are caused by failure to maintain the resting potential, with paradoxical depolarization in low K+. Remarkably, 24 out of 25 HypoPP mutations are R/X substitutions in S4 segments of voltage-sensing domains of CaV1.1 (70% of cases) or NaV1.4 (10% of cases). Expression studies in oocytes and murine muscle show anomalous gating pore leakage currents (ω-pore) for six of eight CaV1.1-HypoPP mutations, with one exception being the charge-conserving R897K. The proposed consensus pathomechanism, whereby a gating pore leak predisposes to paradoxical depolarization in low K+, is now verified by continuous recording of Vm. Selective measurement of voltage-dependent Ca2+ release, in “healthy appearing” HypoPP fibers, shows only a modest decrease in the Ca2+-dependent peak fluorescence (Oregon green 488/EGTA), and supports the notion that stabilizing Vrest will be sufficient to prevent low-K+–induced loss of force. In our knockin mouse models of HypoPP (CaV1.1-R528H and NaV1.4-R669H), pretreatment with K+-channel openers protects against the loss of force with a 2 mM K+ challenge. Alternatively, gene editing offers the possibility of sustained protection from attacks of weakness, and may prevent the late-onset permanent myopathy. In a proof-of-principle study of cultured myoblasts and in vivo electroporation, we show selective editing of the mutant HypoPP allele, without compromise of the WT allele, using CRISPR/Cas-mediated indel formation to destroy the HypoPP allele or a CRISPR/Cas base editor to correct the missense mutation.

scholarly journals The role of action potential changes in depolarization-induced failure of excitation contraction coupling in mouse skeletal muscle

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Xueyong Wang ◽  
Murad Nawaz ◽  
Chris DuPont ◽  
Jessica H Myers ◽  
Steve RA Burke ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Simultaneous Recording ◽  
Periodic Paralysis ◽  
Resting Potential ◽  
Charge Movement ◽  
Vigorous Exercise ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Gating Charge ◽  
Rapid Kinetics

Excitation-contraction coupling (ECC) is the process by which electrical excitation of muscle is converted into force generation. Depolarization of skeletal muscle resting potential contributes to failure of ECC in diseases such as periodic paralysis, intensive care unit acquired weakness and possibly fatigue of muscle during vigorous exercise. When extracellular K+ is raised to depolarize the resting potential, failure of ECC occurs suddenly, over a narrow range of resting potentials. Simultaneous imaging of Ca2+ transients and recording of action potentials (APs) demonstrated failure to generate Ca2+ transients when APs peaked at potentials more negative than –30mV. An AP property that closely correlated with failure of the Ca2+ transient was the integral of AP voltage with respect to time. Simultaneous recording of Ca2+ transients and APs with electrodes separated by 1.6mm revealed AP conduction fails when APs peak below –21mV. We hypothesize propagation of APs and generation of Ca2+ transients are governed by distinct AP properties: AP conduction is governed by AP peak, whereas Ca2+ release from the sarcoplasmic reticulum is governed by AP integral. The reason distinct AP properties may govern distinct steps of ECC is the kinetics of the ion channels involved. Na channels, which govern propagation, have rapid kinetics and are insensitive to AP width (and thus AP integral) whereas Ca2+ release is governed by gating charge movement of Cav1.1 channels, which have slower kinetics such that Ca2+ release is sensitive to AP integral. The quantitative relationships established between resting potential, AP properties, AP conduction and Ca2+ transients provide the foundation for future studies of failure of ECC induced by depolarization of the resting potential.

scholarly journals Disrupted coupling of gating charge displacement to Na+ current activation for DIIS4 mutations in hypokalemic periodic paralysis

2014 ◽  
Vol 144 (2) ◽  
pp. 137-145 ◽  
Author(s):  
Wentao Mi ◽  
Volodymyr Rybalchenko ◽  
Stephen C. Cannon
Keyword(s):  
Periodic Paralysis ◽  
Specific Conductance ◽  
Resting Potential ◽  
Missense Mutations ◽  
Na Current ◽  
Hypokalemic Periodic Paralysis ◽  
Gating Charge ◽  
Arginine Residues ◽  
Charge Displacement ◽  
Low K

Missense mutations at arginine residues in the S4 voltage-sensor domains of NaV1.4 are an established cause of hypokalemic periodic paralysis, an inherited disorder of skeletal muscle involving recurrent episodes of weakness in conjunction with low serum K+. Expression studies in oocytes have revealed anomalous, hyperpolarization-activated gating pore currents in mutant channels. This aberrant gating pore conductance creates a small inward current at the resting potential that is thought to contribute to susceptibility to depolarization in low K+ during attacks of weakness. A critical component of this hypothesis is the magnitude of the gating pore conductance relative to other conductances that are active at the resting potential in mammalian muscle: large enough to favor episodes of paradoxical depolarization in low K+, yet not so large as to permanently depolarize the fiber. To improve the estimate of the specific conductance for the gating pore in affected muscle, we sequentially measured Na+ current through the channel pore, gating pore current, and gating charge displacement in oocytes expressing R669H, R672G, or wild-type NaV1.4 channels. The relative conductance of the gating pore to that of the pore domain pathway for Na+ was 0.03%, which implies a specific conductance in muscle from heterozygous patients of ∼10 µS/cm2 or 1% of the total resting conductance. Unexpectedly, our data also revealed a substantial decoupling between gating charge displacement and peak Na+ current for both R669H and R672G mutant channels. This decoupling predicts a reduced Na+ current density in affected muscle, consistent with the observations that the maximal dV/dt and peak amplitude of the action potential are reduced in fibers from patients with R672G and in a knock-in mouse model of R669H. The defective coupling between gating charge displacement and channel activation identifies a previously unappreciated mechanism that contributes to the reduced excitability of affected fibers seen with these mutations and possibly with other R/X mutations of S4 of NaV, CaV, and KV channels associated with human disease.

scholarly journals A calcium channel mutant mouse model of hypokalemic periodic paralysis

2012 ◽  
Vol 122 (12) ◽  
pp. 4580-4591 ◽  
Author(s):  
Fenfen Wu ◽  
Wentao Mi ◽  
Erick O. Hernández-Ochoa ◽  
Dennis K. Burns ◽  
Yu Fu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Calcium Channel ◽  
Mutant Mouse ◽  
Periodic Paralysis ◽  
Hypokalemic Periodic Paralysis

Morphologic alteration in the muscles of patients with hypokalemic periodic paralysis or myopathy

1990 ◽  
Vol 48 (3) ◽  
pp. 222-223
Author(s):  
T. Shimizu ◽  
Y. Muranaka ◽  
I. Ohta ◽  
N. Honda
Keyword(s):  
Clinical Manifestations ◽  
Quadriceps Muscle ◽  
Honeycomb Structure ◽  
Periodic Paralysis ◽  
Ultrastructural Changes ◽  
Hypokalemic Periodic Paralysis ◽  
Electron Microscopic ◽  
Tubular Aggregates ◽  
Hypokalemic Myopathy ◽  
Transmission Electron

There have been many reports on ultrastructural alterations in muscles of hypokalemic periodic paralysis (hpp) and hypokalemic myopathy(hm). It is stressed in those reports that tubular structures such as tubular aggregates are usually to be found in hpp as a characteristic feature, but not in hm. We analyzed the histological differences between hpp and hm, comparing their clinical manifestations and morphologic changes in muscles. Materials analyzed were biopsied muscles from 18 patients which showed muscular symptoms due to hypokalemia. The muscle specimens were obtained by means of biopsy from quadriceps muscle and fixed with 2% glutaraldehyde (pH 7.4) and analyzed by ordinary method and modified Golgimethod. The ultrathin section were examined in JEOL 200CX transmission electron microscopy.Electron microscopic examinations disclosed dilated t-system and terminal cistern of sarcoplasmic reticulum (SR)(Fig 1), and an unique structure like “sixad” was occasionally observed in some specimens (Fig 2). Tubular aggregates (Fig 3) and honeycomb structure (Fig 4) were also common characteristic structures in all cases. These ultrastructural changes were common in both the hypokalemic periodic paralysis and the hypokalemic myopathy, regardless of the time of biopsy or the duration of hypokalemia suffered.

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