Skip to main content

Table 5 Rodent RYR1 model systems

From: Preclinical model systems of ryanodine receptor 1-related myopathies and malignant hyperthermia: a comprehensive scoping review of works published 1990–2019

Author/Year Ryr1 variant(s) Title Conclusions
YS mouse (equivalent to Y522S in humans)
 Zullo A, et al. [141] 2018 Y524S Voltage modulates halothane-triggered Ca2+ release in malignant hyperthermia-susceptible muscle Binding of halothane to RyR1 alters the voltage dependence of Ca2+ release in MH-susceptible muscle fibers such that the resting membrane potential becomes a decisive factor for the efficiency of the drug to trigger Ca2+ release
 O-Uchi J, et al. [142] 2017 Y524S Malignant hyperthermia-associated mutation of leaky RyR1 induces mitochondrial Ca2+ overload in the heart Chronic mitochondrial Ca2+ overload via leaky mutant mRyR1 damages cardiac mitochondrial functions/structures, which may alter cytosolic Ca2+ handling, induce cellular oxidation, and increase the arrhythmogenic events in MH
 Abeele FV, et al. [143] 2019 Y524S TRPV1 variants impair intracellular Ca2+ signaling and may confer susceptibility to malignant hyperthermia Trpv1 may be contributing to the mechanism underlying the hyperthermia response of this Y524S Ryr1 model TRPV1 and related mutants could be a new therapeutic target for treating muscle diseases due to altered regulation of Ca2+ release
 Michelucci A, et al. [144] 2017 Y524S Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia Strenuous physical exertion triggers lethal episodes in MH-susceptible mice and these episodes share common features with MH episodes triggered by anesthetics and heat (ie, hyperthermia and rhabdomyolysis)
 Michelucci A, et al. [145] 2017 Y524S Antioxidant Treatment Reduces Formation of Structural Cores and Improves Muscle Function in RYR1(Y522S/WT) Mice NAC administration is beneficial to prevent mitochondrial damage and formation of cores and improve muscle function in RYR1Y522S/WT mice
 Lopez RJ, et al. [146] 2016 Y524S An RYR1 mutation associated with malignant hyperthermia is also associated with bleeding abnormalities Y522S mice had longer bleeding times than their WT littermates. Primary vascular smooth muscle cells from Y524S mice exhibited a higher frequency of subplasmalemmal Ca2+ sparks, leading to a more negative resting membrane potential. The bleeding defect of Y524S mice and of one patient was reversed by treatment with the RYR1 antagonist dantrolene, and Ca2+ sparks in primary vascular smooth muscle cells from Y524S mice were blocked by ryanodine or dantrolene
 O-Uchi J, et al. [147] 2016 Y524S Malignant hyperthermia-associated mutation of RyR1 induces mitochondrial damages and cellular oxidation in the heart Chronic mitochondrial Ca2+ overload via leaky mutant mRyR1 damages cardiac mitochondrial functions/structures, reduces cytosolic Ca2+ buffering capacity and induces cellular oxidation, which may increase arrhythmogenic events in MH
 O-Uchi J, et al. [148] 2014 Y524S RyR1 mutation associated with malignant hyperthermia facilitates catecholaminergic stress-included arrhythmia via mitochondrial injury and oxidative stress Chronic mitochondrial damage by Ca2+ overload via leaky mutant RyR1 induces cellular oxidation, which facilitates catecholaminergic stress-triggered arrhythmia
 Yarotskyy V, et al. [149] 2013 Y524S Accelerated activation of SOCE current in myotubes from two mouse models of anesthetic- and heat-induced sudden death While an increased rate of SOCE current activation is a common characteristic of myotubes derived from Y524S/+ and dCasq-null mice and that the protective effects of azumolene are not due to a direct inhibition of SOCE channels
 Vukcevic M, et al. [150] 2013 Y524S Gain of function in the immune system caused by a ryanodine receptor 1 mutation Y524S mice have a gain in immune functions. Gain-of-function MH-linked RYR1 mutations might offer selective immune advantages to their carriers
 Manno C, et al. [151] 2013 Y524S Altered Ca2+ concentration, permeability and buffering in the myofibre Ca2+ store of a mouse model of malignant hyperthermia Y524S mutation causes greater openness of the RyR1, lowers resting SR Ca2+ and alters SR Ca2+ buffering in a way that copies the functional instability observed upon reduction of calsequestrin content
 Knoblauch M, et al. [152] 2013 Y524S Mice with RyR1 mutation (Y524S) undergo hypermetabolic response to simvastatin An acute dose of simvastatin triggers a hypermetabolic response in YS mice. In isolated YS muscle fibers, simvastatin triggers an increase in cytosolic Ca2+ levels by increasing Ca2+ leak from the sarcoplasmic reticulum (SR). With higher simvastatin doses, a similar cytosolic Ca2+ increase occurs in wild type (WT) muscle fibers. Pre-treatment of YS and WT mice with AICAR prevents the response to simvastatin
 Lanner JT, et al. [153] 2012 Y524S AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation AICAR is probably effective in prophylactic treatment of humans with enhanced susceptibility to exercise- and/or heat-induced sudden death associated with RYR1 mutations
O-Uchi J, et al. [154] 2012 Y524S Malignant hyperthermia mutation of RYR1 (Y522S) increases catecholamine-induced cardiac arrhythmia through mitochondrial injury Chronic mitochondrial damage by Ca2+ overload through leaky mutant RyR1 induces mitochondrial structural and functional disruption, which facilitates arrhythmogenic outbursts under acute catecholaminergic stress
 Loy RE, et al. [155] 2012 Y524S Allele-specific gene silencing in two mouse models of autosomal dominant skeletal myopathy The temperature-dependent increase in resting Ca2+ observed in FDB fibers from YS/+ mice was normalized to WT levels after 2 weeks of treatment with YS allele-specific siRNA
 Wei L, et al. [156] 2011 Y524S Mitochondrial superoxide flashes: metabolic biomarkers of skeletal muscle activity and disease Uncontrolled mitochondrial superoxide production likely contributes to the pathogenic temperature-dependent increase in oxidative stress of RYR1Y524S/WT MH mice
 Corona BT, et al. [157] 2010 Y524S Effect of prior exercise on thermal sensitivity of malignant hyperthermia-susceptible muscle Eccentric, but not concentric, exercise attenuated the thermal sensitivity of MH-susceptible muscle
 Boncompagni S, et al. [158] 2009 Y524S Characterization and temporal development of cores in a mouse model of malignant hyperthermia Initial mitochondrial/SR disruption in confined areas causes significant loss of local Ca2+ sequestration that eventually results in the formation of contractures and progressive degradation of the contractile elements
 Andronache Z, et al. [159] 2009 Y524S A retrograde signal from RyR1 alters DHP receptor inactivation and limits window Ca2+ release in muscle fibers of Y522S RyR1 knock-in mice The increase in uncompensated SR Ca2+ leak observed at rest following transient overexpression of the Y524S RyR1 mutant in myotubes is effectively suppressed after long-term expression of a normal compliment of wild-type and mutant RyR1s in adult muscle fibers of WT/Y524S mice
 Durham WJ, et al. [160] 2008 Y524S RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice Ca2+ release channels in RyR1Y524S/wt mice are leaky, producing elevations in resting Ca2+, ROS, RNS and basal stress at physiologically relevant temperatures. Ca2+ leak enhances RNS production, and subsequent S-nitrosylation of RyR1 further increases Ca2+ leak, resulting in regenerative Ca2+ release that underlies uncontrolled contractions during heat stress
 Corona BT, et al. [161] 2008 Y524S Eccentric contractions do not induce rhabdomyolysis in malignant hyperthermia susceptible mice RYR1Y524S/wt protects skeletal muscle from exercise-induced muscle injury. Findings do not support a direct association between MH susceptibility and contraction-induced rhabdomyolysis when core temperature is maintained at lower physiological temperatures during exercise
 Chelu MG, et al. [162] 2006 Y524S Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse Heterozygous expression of the Y524S mutation confers susceptibility to both heat- and anesthetic-induced MH responses
IT mouse (equivalent to I4898T in humans)
 Lee CS, et al. [163] 2017 I4895T A chemical chaperone improves muscle function in mice with a RyR1 mutation Persistent ER stress/UPR, decreased protein synthesis, mitochondrial ROS production/damage and elevation of proapoptotic markers are defining features of RyR1 myopathy associated with the I4895T mutation in mice, making this myopathy distinct from that of the RyR1 myopathies that arise from Ca2+ leak. Chemical chaperones and ER stress inhibitors may be better suited for mutations in RyR1 that produce ER stress/UPR
 Zvaritch E, et al. [164] 2015 I4895T Muscle spindles exhibit core lesions and extensive degeneration of intrafusal fibers in the Ryr1(I4895T/wt) mouse model of core myopathy Muscle spindles undergo severe deterioration that may precede structural changes in extrafusal myofibers Muscle spindles represent an important early target in Ryr1-related disease pathology
 De Crescenzo V, et al. [165] 2012 I4895T Type 1 ryanodine receptor knock-in mutation causing central core disease of skeletal muscle also displays a neuronal phenotype RyR1 plays a role in voltage-induced Ca2+ release in hypothalamic nerve terminals and a neuronal alteration accompanies the myopathy in IT/+ mice
 Loy RE, et al. [155] 2012 I4895T Allele-specific gene silencing in two mouse models of autosomal dominant skeletal myopathy Altered RyR1 function in FDB fibers of YS/+ and IT/+ knock-in mice can be normalized only two weeks after local in vivo delivery of ASGS siRNAs
 Loy RE, et al. [166] 2011 I4895T Muscle weakness in Ryr1I4895T/WT knock-in mice as a result of reduced ryanodine receptor Ca2+ ion permeation and release from the sarcoplasmic reticulum In vivo muscle weakness observed in IT/+ knock-in mice arises from a reduction in the magnitude and rate of RYR1 Ca2+ release during EC coupling that results from the mutation producing a dominant-negative suppression of RYR1 channel Ca2+ ion permeation
 Boncompagni S, et al. [167] 2010 I4895T The I4895T mutation in the type 1 ryanodine receptor induces fiber-type specific alterations in skeletal muscle that mimic premature aging Muscle fibers from IT/+ mice in a mixed 129S6/SvEvTac and 129S2/SvPasCrl background exhibit structural alterations of the type seen in CCD patients as well as in WT mice at older ages
 Zvaritch E, et al. [168] 2009 I4895T Ca2+ dysregulation in Ryr1(I4895T/wt) mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods The IT/+ mouse line represents a unique and phenotypically valid model of RyR1-related congenital myopathy with minicores, cores, and rods
 Zvaritch E, et al. [30] 2007 I4895T An Ryr1I4895T mutation abolishes Ca2+ release channel function and delays development in homozygous offspring of a mutant mouse line IT/IT mice, in which RyR1-mediated Ca2+ release is abolished without altering the formation of the junctional DHPR-RyR1 macromolecular complex, provide a valuable model for elucidation of the role of RyR1-mediated Ca2+ signaling in mammalian embryogenesis
RC mouse (equivalent in humans)
 Truong KM, et al. [169] 2019 R163C Comparison of Chlorantraniliprole and Flubendiamide Activity Toward Wild-Type and Malignant Hyperthermia-Susceptible Ryanodine Receptors and Heat Stress Intolerance Although nM-μM of either diamide is capable of differentially altering WT and MHS RyR1 conformation in vitro, human RyR1 mutations within putative diamide N- and C-terminal interaction domains do not alter heat stress intolerance in vivo
 Eltit JM, et al. [170] 2013 R163C Nonspecific sarcolemmal cation channels are critical for the pathogenesis of malignant hyperthermia nonselective sarcolemmal cation permeability, separate from the classic STIM/Orai pathway, is activated by SR depletion and plays a critical role in the causing cytosolic Ca2+ and Na + overload both at rest and during the MH crisis
 Estève E, et al. [171] 2012 R163C Malignant hyperthermia mutation alters excitation-coupled Ca2+ entry in MH RyR1-R163C knock-in myotubes Conformational changes induced by the R163C MH mutation alter the retrograde signal that is sent from RYR1 to the DHPR, delaying the inactivation of the DHPR voltage sensor
 Giulivi C, et al. [172] 2011 R163C Basal bioenergetic abnormalities in skeletal muscle from ryanodine receptor malignant hyperthermia-susceptible R163C knock-in mice Chronically elevated resting Ca2+ in R163C skeletal muscle elicited the maintenance of a fast-twitch fiber program and the development of insulin resistance-like phenotype as part of a metabolic adaptation to the R163C RyR1 mutation
 Feng W, et al. [173] 2011 R163C Functional and biochemical properties of ryanodine receptor type 1 channels from heterozygous R163C malignant hyperthermia-susceptible mice R163C channels are inherently more active than WT channels, a functional impairment that cannot be reversed by dephosphorylation with protein phosphatase. Dysregulated R163C channels produce a more overt phenotype in myotubes than in adult fibers in the absence of triggering agents, suggesting tighter negative regulation of R163C-RyR1 within the Ca2+ release unit of adult fibers
 Estève E, et al. [174] 2010 R163C A malignant hyperthermia-inducing mutation in RYR1 (R163C): alterations in Ca2+ entry, release, and retrograde signaling to the DHPR Conformational changes induced by the R163C MH mutation alter the retrograde signal that is sent from RYR1 to the DHPR, delaying the inactivation of the DHPR voltage sensor and enhancing sarcolemmal Ca2+ entry during depolarization
 Bannister RA, et al. [175] 2010 R163C A malignant hyperthermia-inducing mutation in RYR1 (R163C): consequent alterations in the functional properties of DHPR channels Mutations in RYR1 can alter DHPR activity and raise the possibility that this altered DHPR function may contribute to MH episodes
 Cherednichenko G, et al. [176] 2008 R163C Enhanced excitation-coupled calcium entry in myotubes expressing malignant hyperthermia mutation R163C is attenuated by dantrolene Myotubes isolated from mice heterozygous and homozygous for the ryanodine receptor type 1 R163C MH susceptibility mutation show significantly enhanced ECCE rates that could be restored to those measured in wild-type cells after exposure to clinical concentrations of dantrolene
 Yang T, et al. [177] 2006 R163C Pharmacologic and functional characterization of malignant hyperthermia in the R163C RyR1 knock-in mouse The newly developed R163C Het mouse line is a valid animal model for studying the largely unknown pathophysiology of MH
Other rodent models
 Brennan S, et al. [178] 2019 T4706M/Indel (equivalent to T4709M in humans) Mouse model of severe recessive RYR1-related myopathy The first mouse model of severe, early-onset recessive RYR1-RM Mice exhibit clearly observable, early-onset phenotypes, premature mortality and a consistent pattern of myofibre hypotrophy
 Elbaz M, et al. [179] 2019 Q1970fsX16/A4329D (equivalent in humans) Quantitative RyR1 reduction and loss of calcium sensitivity of RyR1Q1970fsX16+ A4329D cause cores and loss of muscle strength The phenotype of the RyR1Q1970fsX16 + A4329D compound heterozygous mice recapitulates the clinical picture of multiminicore patients and provide evidence of the molecular mechanisms responsible for skeletal muscle defects
 Elbaz M, et al. [180] 2019 Q1970fsX16 (equivalent in humans) Quantitative reduction of RyR1 protein caused by a single-allele frameshift mutation in RYR1 ex36 impairs the strength of adult skeletal muscle fibres The RyR1Q1970fsX16 mouse model provides mechanistic insight concerning the phenotype of the parent carrying the RYR1 exon 36 mutation and suggests that in skeletal muscle fibres there is a functional reserve of RyR1
 RYR-1 Foundation [181] 2019 T4706M/S1669C + L1716 del Unpublished - https://wwwryr1org/mice Phenotype includes kyphosis and malocclusion. The model is still being fully characterized
 Dulhunty AF, et al. [182] 2019 P3528S Unpublished - https://wwwryr1org/edamame Phenotype includes mild scoliosis and decreased mobility (heterozygous) and scoliosis, decreased mobility, hang time, and increased calcium sensitivity. The model is still being fully characterized
 Lopez JR, et al. [183] 2018 G2435R Malignant hyperthermia, environmental heat stress, and intracellular calcium dysregulation in a mouse model expressing the pG2435R variant of RYR1 RYR1 G2435R 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 G2434R
 Hernandez-Ochoa EO, et al. [184] 2018 L3625D Loss of S100A1 expression leads to Ca2+ release potentiation in mutant mice with disrupted CaM and S100A1 binding to CaMBD2 of RyR1 RyR1D-S100A1KO muscle fibers exhibit a modest but significant increase in myoplasmic Ca2+ transients and enhanced Ca2+ release flux following field stimulation when compared to fibers from RyR1D mice
 Bannister RA, et al. [185] 2016 E4242G Distinct Components of Retrograde Ca(V)11-RyR1 Coupling Revealed by a Lethal Mutation in RyR1 E4242G markedly reduces L-type current density, CaV11 Po, and CaV11 expression, where this last effect is most likely a consequence of the absence of EC coupling. The effects of E4242G on current density, relative Po, and channel expression are similar to those occurring in dyspedic myotubes
 Hanson MG, et al. [186] 2016 E4242G Potassium dependent rescue of a myopathy with core-like structures in mouse Amelioration of potassium leaks through potassium homeostasis mechanisms may minimize muscle damage of myopathies due to certain RYR1 mutations
 Hanson MG, et al. [187] 2015 E4242G Rectification of muscle and nerve deficits in paralyzed ryanodine receptor type 1 mutant embryos Contractility can be resumed through the masking of a potassium leak, and evoked vesicular release can be resumed via bypassing the defect in RyR1 induced calcium release
 Yuen B, et al. [188] 2012 T4826I Mice expressing T4826I-RYR1 are viable but exhibit sex- and genotype-dependent susceptibility to malignant hyperthermia and muscle damage T4826I mice underscore the importance of gene × environment interactions in expression of clinical and subclinical phenotype, and suggest that individuals with RyR1 mutations may represent particularly vulnerable populations to environmental stressors
 Barrientos GC, et al. [189] 2012 T4826I Gene dose influences cellular and calcium channel dysregulation in heterozygous and homozygous T4826I-RYR1 malignant hyperthermia-susceptible muscle Pronounced abnormalities inherent in T4826I-RYR1 channels confer MHS and promote basal disturbances of excitation-contraction coupling, [Ca2+](rest), and oxygen consumption rates. Considering that both Het and Hom T4826I-RYR1 mice are viable, the remarkable isolated single channel dysfunction mediated through this mutation in S4-S5 cytoplasmic linker must be highly regulated in vivo
 Andersson DC, et al. [190] 2012 S2844A Stress-induced increase in skeletal muscle force requires protein kinase A phosphorylation of the ryanodine receptor The molecular mechanism underlying skeletal muscle inotropy requires enhanced SR Ca2+ release due to PKA phosphorylation of S2844 in RyR1
 Andersson DC, et al. [191] 2011 S2844D Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging 6-month-old mice harboring leaky S2844D mutant channels exhibited skeletal muscle defects comparable to 24-month-old WT mice
 Yamaguchi N, et al. [192] 2011 L3625D Modulation of sarcoplasmic reticulum Ca2+ release in skeletal muscle expressing ryanodine receptor impaired in regulation by calmodulin and S100A1 L3625D removes both an early activating effect of S100A1 and CaM and delayed suppressing effect of CaCaM on RyR1 Ca2+ release
 Felder E, et al. [193] 2002 RYR1/DHPR double KO Morphology and molecular composition of sarcoplasmic reticulum surface junctions in the absence of DHPR and RyR in mouse skeletal muscle RyR nor DHPR, alone or separately, are necessary for T-SR docking and for the targeting and/or association of calsequestrin and triadin in the junctional SR. Both proteins are needed for appropriate muscle development