Malignant hyperthermia, environmental heat stress, and intracellular calcium dysregulation in a mouse model expressing the p.G2435R variant of RYR1

López, José R.; Kaura, Vikas; Diggle, Christine P.; Hopkins, Philip M.; Allen, Paul D.

doi:10.1016/j.bja.2018.07.008

Cited by 58 publications

(86 citation statements)

References 33 publications

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“…As previously mentioned, one hypothesis for the mitochondrial dysfunction in MHS muscle observed here may be the result of chronic elevation in cytosolic Ca 2+ that has been demonstrated in human 28 and porcine 29 MH muscle as well as knock-in mouse models 11,12,30 . Ca 2+ increases mitochondrial activity which can stimulate higher rates of ROS production through complex I, III and, as has been recently shown, complex II of the ETS 31 .…”

Section: Discussionsupporting

confidence: 57%

Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia-susceptible individuals

Chang

Daly

Miller

et al. 2019

British Journal of Anaesthesia

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Section: Discussionsupporting

confidence: 57%

Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia-susceptible individuals

Chang

Daly

Miller

et al. 2019

British Journal of Anaesthesia

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“…13,21 The findings are in contrast to the data from RYR1 knock-in mouse models of MH demonstrating consistent heat intolerance. [23][24][25] To date four murine models have been developed each focusing on a specific variant, the most recent of these involves a variant carried by one of the volunteers in the MHS study group (p.Gly2434Arg), 25 notably this was the volunteer who failed to thermoregulate.…”

Section: Discussionmentioning

confidence: 99%

Thermoregulation and markers of muscle breakdown in malignant hyperthermia susceptible volunteers during an acute heat tolerance test

House

Tipton

Hopkins

et al. 2019

Journal of Science and Medicine in Sport

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Objectives. The study was undertaken to examine the thermal and biochemical responses to a heat tolerance test (HTT) of malignant hyperthermia (MH) susceptible individuals, and compare these with the responses of volunteers who have suffered heat illness (HI) and control volunteers. Methods. Three groups of male volunteers (n=6 in each group) were recruited to the study: MHS-civilian volunteers previously diagnosed as MH susceptible; EHI-military volunteers with a history of exertional HI; CON-military volunteers with no history of HI or MH. For the HTT, volunteers walked on a treadmill at 60 % maximal oxygen uptake in an environmental chamber (mean [SD] temperature 35.5 [0.4] °C, relative humidity 43 [1] %). Measurements were made to assess thermoregulation and biochemistry. Results. There were no differences in deep body temperature, oxygen uptake or serum lactate concentrations between the three groups, although one MHS volunteer and two EHI volunteers failed to thermoregulate. Serum myoglobin concentration and the increase in serum myoglobin was higher in MHS than EHI and CON Post HHT (P<0.05). Conclusion. MH susceptibility does not always predispose an individual to heat intolerance during an acute HTT, but does appear to increase muscle breakdown. The inclusion of serum myoglobin measurements to a HTT may help to distinguish patients that are potentially MHS or have an underlying muscle myopathy, and who otherwise demonstrate thermal tolerance.

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“…One of our primary future directions is therefore to develop new models of RYR1-RM that are better suited to drug discovery and for subsequent testing in mammals. In this vein, there are very recent publications detailing new recessive RYR1-RM mouse models including a p.G2435R mutant (Lopez et al, 2018), a p.A4329D/p.Q1970fsX16 compound heterozygote model (Elbaz et al, 2019), and a p.T4706M/indel compound heterozygote model generated by our group (Brennan et al, 2019). In addition, seven RYR1-RM equivalent mutations in unc-68…”

Section: Discussionmentioning

confidence: 99%

Identification of drug modifiers for RYR1-related myopathy using a multi-species discovery pipeline

Volpatti

Endo

Knox

et al. 2020

eLife

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Ryanodine receptor type I-related myopathies (RYR1-RMs) are a common group of childhood muscle diseases associated with severe disabilities and early mortality for which there are no available treatments. The goal of this study is to identify new therapeutic targets for RYR1-RMs. To accomplish this, we developed a discovery pipeline using nematode, zebrafish, and mammalian cell models. We first performed large-scale drug screens in C. elegans which uncovered 74 hits. Targeted testing in zebrafish yielded positive results for two p38 inhibitors. Using mouse myotubes, we found that either pharmacological inhibition or siRNA silencing of p38 impaired caffeine-induced Ca2+ release from wild type cells while promoting intracellular Ca2+ release in Ryr1 knockout cells. Lastly, we demonstrated that p38 inhibition blunts the aberrant temperature-dependent increase in resting Ca2+ in myotubes from an RYR1-RM mouse model. This unique platform for RYR1-RM therapy development is potentially applicable to a broad range of neuromuscular disorders.

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Malignant hyperthermia, environmental heat stress, and intracellular calcium dysregulation in a mouse model expressing the p.G2435R variant of RYR1

Abstract: RYR1 pG2435R mice demonstrated gene dose-dependent in vitro and in vivo responses to pharmacological and environmental stressors that parallel those seen in patients with the human RYR1 variant p.G2434R.

Cited by 58 publications

References 33 publications

Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia-susceptible individuals

Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia-susceptible individuals

Thermoregulation and markers of muscle breakdown in malignant hyperthermia susceptible volunteers during an acute heat tolerance test

Identification of drug modifiers for RYR1-related myopathy using a multi-species discovery pipeline

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