Physiological basis for muscle stiffness and weakness in a knock-in M1592V mouse model of hyperkalemic periodic paralysis

Khogali, Shiemaa; Lucas, Brooke; Ammar, Tarek; DeJong, Danica; Barbalinardo, Michael; Hayward, Lawrence J.; Renaud, Jean‐Marc

doi:10.14814/phy2.12656

Cited by 6 publications

(5 citation statements)

References 26 publications

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“…The lower tetanic force, greater fiber inexcitability, less negative resting E M , and lower overshoot of HyperKPP muscles compared with their wild type counterpart reported here are similar to previous reports where the cause has been fully discussed (Hayward et al, 2008;Clausen et al, 2011;Lucas et al, 2014;Ammar et al, 2015;Khogali et al, 2015). This study now reveals the extent of which HyperKPP muscles are more Ca 2+ sensitive than wild type muscles.…”

Section: Salbutamol Effectssupporting

confidence: 91%

Lower Ca2+ enhances the K+-induced force depression in normal and HyperKPP mouse muscles

Uwera

Ammar

McRae

et al. 2020

Journal of General Physiology

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Hyperkalemic periodic paralysis (HyperKPP) manifests as stiffness or subclinical myotonic discharges before or during periods of episodic muscle weakness or paralysis. Ingestion of Ca2+ alleviates HyperKPP symptoms, but the mechanism is unknown because lowering extracellular [Ca2+] ([Ca2+]e) has no effect on force development in normal muscles under normal conditions. Lowering [Ca2+]e, however, is known to increase the inactivation of voltage-gated cation channels, especially when the membrane is depolarized. Two hypotheses were tested: (1) lowering [Ca2+]e depresses force in normal muscles under conditions that depolarize the cell membrane; and (2) HyperKPP muscles have a greater sensitivity to low Ca2+-induced force depression because many fibers are depolarized, even at a normal [K+]e. In wild type muscles, lowering [Ca2+]e from 2.4 to 0.3 mM had little effect on tetanic force and membrane excitability at a normal K+ concentration of 4.7 mM, whereas it significantly enhanced K+-induced depression of force and membrane excitability. In HyperKPP muscles, lowering [Ca2+]e enhanced the K+-induced loss of force and membrane excitability not only at elevated [K+]e but also at 4.7 mM K+. Lowering [Ca2+]e increased the incidence of generating fast and transient contractures and gave rise to a slower increase in unstimulated force, especially in HyperKPP muscles. Lowering [Ca2+]e reduced the efficacy of salbutamol, a β2 adrenergic receptor agonist and a treatment for HyperKPP, to increase force at elevated [K+]e. Replacing Ca2+ by an equivalent concentration of Mg2+ neither fully nor consistently reverses the effects of lowering [Ca2+]e. These results suggest that the greater Ca2+ sensitivity of HyperKPP muscles primarily relates to (1) a greater effect of Ca2+ in depolarized fibers and (2) an increased proportion of depolarized HyperKPP muscle fibers compared with control muscle fibers, even at normal [K+]e.

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Section: Salbutamol Effectssupporting

confidence: 91%

Lower Ca2+ enhances the K+-induced force depression in normal and HyperKPP mouse muscles

Uwera

Ammar

McRae

et al. 2020

Journal of General Physiology

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“…Furthermore, the higher number of type IIA in normal soleus is associated with a pump content that is two times greater than in normal EDL ( Clausen et al, 2011 ; Ammar et al, 2015 ). Finally, in a hyperkalemic periodic paralysis (HyperKPP) mouse model, the number of EDL fibers that express type IIA myosin is ∼60% ( Khogali et al, 2015 ) compared with 16% in normal EDL muscle (this study); again, the greater number of type IIA fibers in HyperKPP EDL is associated with a pump content that is two times greater than in normal EDL ( Clausen et al, 2011 ; Ammar et al, 2015 ). Together, these facts suggest that fibers expressing type IIA myosin contain more Na + K + pump than fibers expressing type IIB myosin, and as the number of fibers expressing type IIA myosin increases to 95% in denervated EDL, there is a concomitant increase in pump content.…”

Section: Discussionmentioning

confidence: 66%

Angiotensin 1–7 prevents the excessive force loss resulting from 14- and 28-day denervation in mouse EDL and soleus muscle

Albadrani

Ammar

Bäder

et al. 2021

Journal of General Physiology

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Denervation leads to muscle atrophy, which is described as muscle mass and force loss, the latter exceeding expectation from mass loss. The objective of this study was to determine the efficiency of angiotensin (Ang) 1–7 at reducing muscle atrophy in mouse extensor digitorum longus (EDL) and soleus following 14- and 28-d denervation periods. Some denervated mice were treated with Ang 1–7 or diminazene aceturate (DIZE), an ACE2 activator, to increase Ang 1–7 levels. Ang 1–7/DIZE treatment had little effect on muscle mass loss and fiber cross-sectional area reduction. Ang 1–7 and DIZE fully prevented the loss of tetanic force normalized to cross-sectional area and accentuated the increase in twitch force in denervated muscle. However, they did not prevent the shift of the force–frequency relationship toward lower stimulation frequencies. The Ang 1–7/DIZE effects on twitch and tetanic force were completely blocked by A779, a MasR antagonist, and were not observed in MasR−/− muscles. Ang 1–7 reduced the extent of membrane depolarization, fully prevented the loss of membrane excitability, and maintained the action potential overshoot in denervated muscles. Ang 1–7 had no effect on the changes in α-actin, myosin, or MuRF-1, atrogin-1 protein content or the content of total or phosphorylated Akt, S6, and 4EPB. This is the first study that provides evidence that Ang 1–7 maintains normal muscle function in terms of maximum force and membrane excitability during 14- and 28-d periods after denervation.

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“…The potassium‐induced weakness assay was performed as described previously for the M1592V HyperPP mouse model, with concomitant changes in calcium included as this exacerbates the difference between mutant and WT mice. 17 , 18 , 23 , 24 The baseline bath solution contained NaCl 118 mmol; KCl 4.75 mmol; MgSO 4 1.18 mmol; CaCl 2 2.54 mmol; NaH 2 PO 4 1.18 mmol; glucose 10 mmol; NaHCO 3 24.8 mmol. The high‐potassium, low‐calcium solution differed from the baseline bath solution as follows: NaCl 113 mmol; KCl 10 mmol; MgCl 2 1.04 mmol; CaCl 2 1.3 mmol.…”

Section: Methodsmentioning

confidence: 99%

“…The potassium-induced weakness assay was performed as described previously for the M1592V HyperPP mouse model, with concomitant changes in calcium included as this exacerbates the difference between mutant and WT mice. 17,18,23,24 The baseline bath solution contained NaCl 118 CaCl 2 was increased to 4 mmol. Muscles were not exposed to insulin or curare.…”

Section: Muscle Force Measurements On Soleus Muscle Ex Vivomentioning

confidence: 99%

Ageing contributes to phenotype transition in a mouse model of periodic paralysis

Suetterlin

Tan

Männikkö

et al. 2021

JCSM Rapid Communications

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Background Periodic paralysis (PP) is a rare genetic disorder in which ion channel mutation causes episodic paralysis in association with hyper-or hypokalaemia. An unexplained but consistent feature of PP is that a phenotype transition occurs around the age of 40, in which the severity of potassium-induced muscle weakness declines but onset of fixed, progressive weakness is reported. This phenotype transition coincides with the age at which muscle mass and optimal motor function start to decline in healthy individuals. We sought to determine if the phenotype transition in PP is linked to the normal ageing phenotype transition and to explore the mechanisms involved. Methods A mouse model of hyperkalaemic PP was compared with wild-type littermates across a range of ages (13-104 weeks). Only male mice were used as penetrance is incomplete in females. We adapted the muscle velocity recovery cycle technique from humans to examine murine muscle excitability in vivo. We then examined changes in potassium-induced weakness or caffeine contracture force with age using ex vivo muscle tension testing. Muscles were further characterized by either Western blot, histology or energy charge measurement. For normally distributed data, a student's t-test (± Welch correction) or one-or two-way analysis of variance (ANOVA) was performed to determine significance. For data that were not normally distributed, Welch rank test, Mann Whitney U test or Kruskal-Wallis ANOVA was performed. When an ANOVA was significant (P < 0.05), post hoc Tukey testing was used. Results Both WT (P = 0.009) and PP (P = 0.007) muscles exhibit increased resistance to potassium-induced weakness with age. Our data suggest that healthy-old muscle develops mechanisms to maintain force despite sarcolemmal depolarization and sodium channel inactivation. In contrast, reduced caffeine contracture force (P = 0.00005), skeletal muscle energy charge (P = 0.004) and structural core pathology (P = 0.005) were specific to Draggen muscle, indicating that they are caused, or at least accelerated by, chronic genetic ion channel dysfunction. Conclusions The phenotype transition with age is replicated in a mouse model of PP. Intrinsic muscle ageing protects against potassium-induced weakness in HyperPP mice. However, it also appears to accelerate impairment of sarcoplasmic reticulum calcium release, mitochondrial impairment and the development of core-like regions, suggesting acquired RyR1 dysfunction as the potential aetiology. This work provides a first description of mechanisms involved in phenotype transition with age in PP. It also demonstrates how studying phenotype transition with age in monogenic disease can yield novel insights into both disease physiology and the ageing process itself.

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Physiological basis for muscle stiffness and weakness in a knock-in M1592V mouse model of hyperkalemic periodic paralysis

Cited by 6 publications

References 26 publications

Lower Ca2+ enhances the K+-induced force depression in normal and HyperKPP mouse muscles

Lower Ca2+ enhances the K+-induced force depression in normal and HyperKPP mouse muscles

Angiotensin 1–7 prevents the excessive force loss resulting from 14- and 28-day denervation in mouse EDL and soleus muscle

Ageing contributes to phenotype transition in a mouse model of periodic paralysis

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