Porcine Stress Syndrome Research Articles

Porcine stress syndrome

This datasheet on porcine stress syndrome covers Identity, Overview, Distribution, Hosts/Species Affected, Diagnosis, Pathology, Epidemiology, Impacts, Prevention/Control, Further Information.

Wild pigs (Sus scrofa) population as reservoirs for deleterious mutations in the RYR1 gene associated with Porcine Stress Syndrome

Porcine Stress Syndrome (PSS) is a disorder codified by the ryanodine receptor 1 gene (RYR1) and affects both animal welfare and the quality of the meat product. As a consequence, individuals with this syndrome generate great worldwide economic losses in the porcine industry. In Argentina, the Buenos Aires Province is the most involved on this activity, and productions are to be in open field with a higher frequency of pigs with diverse pathologies. On the other hand, the biggest and oldest wild pigs population is located on the Atlantic coast of Buenos Aires Province, which presents a continuous bidirectional flow of individuals with the productive areas nearby. The aim of this study is to detect the presence of the RYR1 deleterious allele in the wild population from the Atlantic coast of Buenos Aires, in order to evaluate its possible role as a genetic reservoir for said allele. For this purpose, 106 wild pigs from 28 sites were studied, finding a 6.6% of carrier individuals, indicating that the wild population is not free of this allele. This constitutes the first analysis to detect the presence of the RYR1 deleterious allele, associated to the PSS in wild pigs from Argentina, being one of the few studies to report it worldwide and suggesting wild pigs populations to be a possible genetic reservoir for this disease.

Análisis de polimorfismos en los genes SOX6 y Ryr1 y su relación con la calidad de carne de cerdo

Se estudió la incidencia de polimorfismos de los genes Ryr1 y SOX6 en una población porcina del noreste entrerriano. Ambos genes están relacionados con la calidad de carne, Ryr1 es responsable del síndrome de estrés porcino y carnes PSE, mientras que SOX6 es un factor de transcripción importante en la diferenciación de fibras musculares. Se analizó el efecto de dos SNPs de SOX6 y uno de Ryr1 con respecto a los atributos de calidad. Los resultados mostraron que el pH y la CRA se vieron influenciados significativamente con SOX6a mientras que SOX6b solo se vinculó con el pH. La implementación de este tipo de estrategias contribuye al crecimiento de la industria porcina y a responder a las exigencias de los consumidores. Este trabajo sugiere que la selección de genotipos portadores de alelos C para Ryr1, A para SOX6a y C para SOX6b podría mejorar la producción de carne fresca de buena calidad.

Effect of adaptogens on the quality of pig meat

The specificity of post-mortem redox processes in pork with the development of PSS (Porcine Stress Syndrome), which is the syndrome of pig stress, is considered. Pre-slaughter stress leads to the increased breakdown of glycogen, a slight decrease in the pH of muscle tissue during autolysis and a significant pH shift to the acidic side. To study the physicochemical parameters of muscle tissue after deboning, samples of the longest muscle were taken at the level of 9–12 thoracic vertebrae, 400 g of each half-carcass. Changes in the pH of meat in the experimental groups correlated with the indicators of volatile fatty acids (VFA), which considered the indicator of meat quality. The level of VFA in the group with a dosage of 10 mg/kg of lithium ascorbate was 3.07 % lower than in the control. We also recorded the higher pH values in the first experimental group (by 3 % relative to the control group).When the pH balance shifted to the acidic side, the acidosis occurs, which negatively affected muscle contraction in living organisms. In post-slaughter period the acidosis prevented the contraction of muscle fibers, which increased the organoleptic quality of meat products. The lithium ascorbate prevented the activation of metabolic processes under the action of catecholamines and reduced the level of organic acids in muscle fibers with increasing the stress resistance. The use of lithium ascorbate as a stress protector could reduce these negative effects and increase the organoleptic quality. We suggested to include lithium ascorbate in a standard diet in a dosage of 10 mg/kg of the body weight during the entire feeding period. The presented scheme of lithium ascorbate usage will allow achieving the best organoleptic and physicochemical qualities of pig meat products.

Early Development, Identification of Mode of Action, and Use of Dantrolene Sodium: The Role of Keith Ellis, Ph.D.

Dantrolene-a nitrofurantoin derivative-was developed by Snyder et al. in 1967. After initial discovery of its muscle relaxation potential, investigations in a number of species demonstrated dose-dependent reductions in skeletal muscle tone that were long lasting, relatively nontoxic, and free of adverse effects such as respiratory impairment. Ellis et al. then published a number of papers investigating the means by which dantrolene produced these effects. Using a series of classic physiologic models, Ellis investigated potential sites of action for the new drug, eventually narrowing this down to the intracellular calcium-release mechanism. Ellis went on to play a pivotal role in the discovery of dantrolene's effectiveness for the treatment of malignant hyperthermia, after reading a scientific bulletin about muscle rigidity in pigs affected by porcine stress syndrome, contacting Gaisford Harrison and sending dantrolene to him for trial.

Associations of biochemical changes and maternal traits with mutation 1843 (C>T) in the RYR1 gene as a common cause for porcine stress syndrome.

Stress syndrome is usually caused by a mutation in the ryanodine receptor gene (ryr1) and it is widely studied in humans and swine populations. The protein product of this gene plays a crucial role in the regulation of calcium transport in muscle cells. A G>T mutation in the human ryr1 gene, which results in the replacement of a conserved arginine at position 614 where a leucine occurs at the same position as the previously identified Arg→Cys mutation reported in all cases of porcine stress syndrome (PSS). Porcine stress syndrome affects biochemical pathways in stress-susceptible individuals during a stress episode and some biochemical parameters that were used as markers for diagnostic purposes. Also, PSS has remarkable influence on the maternal characteristics of sows. This study dealt with different genotypes for PSS and its association with possible biochemical changes and maternal traits of sows. Seventy-three reproductive sows genotyped for PSS by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were included in this survey. Sixty of them were stress-free (NN), 11 were heterozygous carriers (Nn) and two animals were homozygous (nn) for the 1843 (C>T) mutation. Significant differences in non stress induced animals with different PSS genotypes were found in the values of creatine phoshokinase (CPK), lactate dehydrogenase (LDH), alkaline phosphatase (AP) and aspartate aminotransferase (AST). Regarding the maternal traits, our study showed that stress susceptible animals (nn) have an increased number of stillborn piglets and a reduced number of newborn piglets compared with heterozygous and normal animals.

A Brief Review of Infrequent Spontaneous Findings, Peculiar Anatomical Microscopic Features, and Potential Artifacts in Göttingen Minipigs.

Minipigs are now used in greater numbers in contract research organizations (CROs) as well as in the pharmaceutical industry. Most CROs or pharmaceutical companies use the Göttingen minipig, which displays a number of important background lesions. This review will discuss some of the more infrequent minipig background changes. Porcine stress syndrome is an autosomal recessive pharmacogenetic disorder in minipigs causing malignant hyperthermia and muscle necrosis. Possible triggers, clinical pathology as well as heart, muscle, liver, lung, and kidney histopathology are discussed. Additional spontaneous changes, background findings, and peculiar anatomical and histological features include thrombocytopenic purpura syndrome, spontaneous glomerulonephritis, osteochondritis, ellipsoids, or Schweigger-Seidel sheaths in the spleen, as well as the presence of a perimesenteric plexus adjacent to mesenteric lymph nodes, squamous epithelial metaplasia of the salivary gland, and cupping of the optic disk in the minipig eye. In order to maximize the data gained from minipig studies, the interpretation of pathology findings requires the input of experienced pathologists who understand the significance of artifacts and spontaneous, background lesions in minipigs and can distinguish these from induced lesions.

The effects of ryanodine receptor (RYR1) mutation on natural killer cell cytotoxicity, plasma cytokines and stress hormones during acute intermittent exercise in pigs

Stress susceptibility has been mapped to a single recessive gene, the ryanodine receptor 1 (RYR1) gene or halothane (Hal) gene. Homozygous (Halnn), mutated pigs are sensitive to halothane and susceptible to Porcine Stress Syndrome (PSS). Previous studies have shown that stress-susceptible RYR1 gene mutated homozygotes in response to restraint stress showed an increase in natural killer cell cytotoxicity (NKCC) accompanied by more pronounced stress-related hormone and anti-inflammatory cytokine changes. In order to determine the relationship of a RYR1 gene mutation with NKCC, plasma cytokines and stress-related hormones following a different stress model — exercise — 36 male pigs (representing different genotypes according to RYR1 gene mutation: NN, homozygous dominant; Nn, heterozygous; nn, homozygous recessive) were submitted to an intermittent treadmill walking. During the entire experiment the greatest level of NKCC and the greatest concentrations of interleukin (IL-) 6, IL-10, IL-12, interferon (IFN-)γ and tumor necrosis factor-α and stress-related hormones (adrenaline, prolactin, beta-endorphin) were observed in nn pigs, and the greatest concentration of IL-1 and growth hormone in NN pigs. Immunostimulatory effects of intermittent exercise on NKCC in nn pigs were concomitant with increases in IL-2, IL-12 and IFN-γ, the potent NKCC activators. Our findings suggest that stress-susceptible pigs RYR1 gene mutated pigs develop a greater level of NKCC and cytokine production in response to exercise stress. These results suggest that the heterogeneity of immunological and neuroendocrine response to exercise stress in pigs could be influenced by RYR1 gene mutation.

ABOUT THE QUALITY OF MEAT WITH PSE AND DFD PROPERTIES

Abstract: The use of modern technologies in meat production often leads to the formation of raw meat with uncharacteristic course of autolysis, one raw meat being characterized by a low pH value (less than 5.2), it is pale, flabby and watery (Pale, Soft, Exudative (PSE) with a loose consistency. Meat juice is allocated and meat has a sour smell. Other meat has a high ultimate pH (more than 6.2), it is dark, tough and dry (Dark, Firm, Dry (DFD) with coarse fiber and sticky. One of the quality indices enabling to identify meat into PSE and DFD groups is color. The pH of meat correlates with the loss of meat juice and color. Pork protein with PSE defect is characterized by a small amount of fractions with a high molecular weight and a large proportion of protein fractions with the molecular weight from 100 to 50 kDa. During meat production the technological solution for the rational use of raw meat with deviations in the autolysis process can be modes of heat treatment and the use of food additives. Stress causes a significant impact on the meat quality of slaughtered animals. The appearance of meat with PSE quality is associated with the animal susceptibility and its response to the stressful situation, and the specificity of biochemical processes in pork is caused by the development of a stress syndrome PSS (Porcine Stress Syndrome), the syndrome of poor adaptation. The meat quality is affected by breed, for example, hybrid pigs are superior to pure bred in technological properties and meat productivity. The meat of pigs of large white x Landrace x Duroc refers to NOR meat, which makes it more valuable. Due to the fact that the susceptibility of pigs to stress is inherited as a single recessive gene, the pigs are divided by genotype into two groups: stress sensitive and stress resistant. It has been shown that the activity of antiperoxide enzymes is higher in stress resistant broiler chickens than in stress sensitive ones.

Frequency of the malignant hyperthermia gene in the South African pig industry

Porcine stress syndrome (PSS) is a genetic disorder caused by a recessive mutation in the halothane (HAL) gene and results in sudden death of pigs when placed under stress during transport and pre-slaughtering conditions. Animals that are affected by this mutation tend to develop pale, soft and exudative (PSE) meat, which results in an economic loss. In South Africa, the frequency of the number of carriers (Nn) and recessive (nn) pigs has increased by 21% to 30% from 2000 to 2003. This study aims to determine the prevalence of the malignant hyperthermia (MH) gene in breeding boars at nucleus or seed-stock level, and the prevalence at commercial abattoirs across the South African pig industry. Results indicate a low number of carriers (Nn = 17) and recessive (nn = 1) pigs at seed-stock level. For commercial abattoirs, 96.4% of the pigs tested did not carry the mutation. The low incidence of the MH mutation from breeding stock should eliminate a contributory factor to PSE meat in South Africa. Transport over long distances to abattoirs may ultimately have an effect on pork obtained even from non-carriers of the MH mutation. Keywords : MH gene, halothane gene, PSE meat, ryanodine receptor, seed stock herds

Dantrolene

The porcine stress syndrome is a major cause of poor meat quality and death in the pork industry. It is known to be more prevalent in some pig strains than others,1 and susceptible animals can be identified by a challenge with halothane, which results in striking elevation in body temperature. This scenario parallels the clinical entity of familial malignant hyperthermia on exposure to general anesthetics, which was one of the earliest recognized human pharmacogenetic syndromes. We now know that affected pigs and people share the same molecular mechanism, mutations in the sarcoplasmic reticulum (SR) calcium release channel of skeletal muscle encoded by RYR1 .2,3 In the pig world, selective breeding programs have been used to develop strains resistant to malignant hyperthermia. In humans, malignant hyperthermia is an anesthetic emergency and is treated by immediate intravenous administration of dantrolene, which is effective and thought to be safe. Chronic oral dantrolene is also approved to treat severe muscle spasticity, and, in this setting, the limiting toxicity is hepatitis, which can be fulminant and fatal in up to 1% of exposed subjects. Article see p 875 Abrupt membrane depolarization (excitation) in skeletal or in cardiac muscle results in calcium release from SR stores via ryanodine receptor (RyR) calcium release channels, and the ensuing rise in intracellular calcium then activates the contractile apparatus. The details of the way in which excitation couples to contraction differs somewhat in the 2 types of muscle (in the heart, but not in skeletal muscle, calcium influx via voltage-gated Cav1.2 channels is required to activate RyR channels; Figure), and there are different genes encoding the channels, RYR1 in skeletal muscle and RYR2 in cardiac muscle. Early studies of the mechanism of action of dantrolene highlighted its ability to decouple excitation from contraction in skeletal muscle, …

Atividades de creatina quinase e lactato desidrogenase na identificação de frangos com estresse e filés PSE (pale, soft, exudative)

Porcine Stress Syndrome (PSS) is a syndrome that occurs in pigs. PSS animals are sensitive to the anesthetic halothane, have higher activities of Creatine Kinase (CK) and Lactate Dehydrogenase (LDH) and are predisposed to the development of PSE (Pale, Soft, Exudative) meat, compromising the meat quality. In chickens, little is known about the relationship between sensitivity to and halothane changes in the activities of these enzymes with the occurrence of PSE meat. The aim of this study was to evaluate the CK and LDH activities in sensitive and non-sensitive halothane chickens and for stress susceptibility identification and PSE meat development. Birds were exposed to halothane at a 3.0 % concentration in pure O2 for 5 min. Afterwords, they were classified into groups: sensitive to halothane (HAL +) (stiffening of the lower limbs) and Non-sensitive (HAL-) (no hardening). After 3 h and 48 h to the test, blood was collected from the wing vein gill, serum extracted and stored at –22 °C until analysis of CK and LDH. No differences were observed (p ? 0.05) in CK activity for HAL+ and HAL- groups. However, differences (p ? 0.05) were observed the LDH activity at 3 h and 48 h, and 44.2 % and 66.1 % higher for the group HAL +, respectively. The determination of lactate dehydrogenase activity indicates to be an alternative to identify animals susceptible to stress thus prone to produce PSE meat.

Skeletal muscle calcium channel ryanodine and the development of pale, soft, and exudative meat in poultry

The development of pale, soft, and exudative (PSE) breast fillet meat has become an economic burden for the poultry industry worldwide. PSE meat results in 1.0-1.5% loss in moisture and carcass weight, and a 2010 estimate of the Brazilian annual production put the economic loss due to PSE at over US$30 million. In the USA, PSE has caused an annual loss of up to US$200 million to the poultry industries. The underlying causes of the color abnormality in PSE meat are not fully understood. However, the likely physiological origin of PSE broiler meat is an excessive release of Ca(2+) promoted by a genetic mutation of the ryanodine receptor (RYR), a Ca(2+)-channel protein in the skeletal muscle sarcoplasmic reticulum. In pigs, the genetic cause of PSE meat has been identified as a point mutation in the RYR1 gene at nucleotide 1843, which causes an amino acid substitution (Arg615 to Cys615) in the RYR. This mutation leads to an alteration in Ca(2+) homeostasis, hypermetabolism, intense muscle contraction, and malignant hyperthermia in pigs susceptible to porcine stress syndrome. An understanding of this process represents the basis for breeding strategies aimed at eliminating the RYR1 mutation from global pig populations, a strategy that the poultry industry intends to emulate. The aim of this study was to review the subject, with an emphasis on the most recent developments in the field.

Genotyping of the porcine ryanodine receptor 1 (RYR1) and estrogen receptor 1 (ESR1) genes by high resolution melting (HRM) approach

During the last decade, DNA mutations in the porcine ryanodine receptor 1 gene (RYR1, C1843T) and the estrogen receptor 1 gene (ESR1, T1665G), have been widely used in marker-assisted selection (MAS) for the pig industry. These 2 well-characterized SNPs in RYR1 and ESR1 are responsible for porcine stress syndrome (PSS) and litter size, respectively. Here, we describe a reliable, high-efficiency method for the genotyping of these 2 genes using the high-resolution melting (HRM) method. The HRM approach exhibited high-accuracy and repeatability, comparable with the classic PCR-restriction fragment length polymorphism (PCR-RFLP) approach, and is potentially suitable for large-scale genotyping in commercial pig farms.

Porcine stress syndrome (PSS) in mangalitsa pigs

Porcine stress syndrome (PSS) is one kind of molecular genetics defect which will cause malignant hyperthermia syndrome in pigs. It was reported that mutation of pig rynodine receptor (RYR1) gene is the main reason for PSS. The aim of this study was to test the RYR1 genotype of 10 Mangalitsa pigs using a polymerase chain reaction-restriction endonuclease fragment length polymorphism (PCR-RFLP) technique, which is a reliable and simple method for RYR1 gene testing. Extraction of DNA was done by using hair follicles. The results showed that the RYR1 genotype of all the 10 porcine cases were negative. These results suggested that Mangalitsa pig could be one of the porcine breeds selectively bred for medical and clinically experiments.

Brain pericytes from stress-susceptible pigs increase blood-brain barrier permeability in vitro

BackgroundThe function of pericytes remains questionable but with improved cultured technique and the use of genetically modified animals, it has become increasingly clear that pericytes are an integral part of blood–brain barrier (BBB) function, and the involvement of pericyte dysfunction in certain cerebrovascular diseases is now emerging. The porcine stress syndrome (PSS) is the only confirmed, homologous model of malignant hyperthermia (MH) in veterinary medicine. Affected animals can experience upon slaughter a range of symptoms, including skeletal muscle rigidity, metabolic acidosis, tachycardia and fever, similar to the human syndrome. Symptoms are due to an enhanced calcium release from intracellular stores. These conditions are associated with a point mutation in ryr1/hal gene, encoding the ryanodine receptor, a calcium channel. Important blood vessel wall muscle modifications have been described in PSS, but potential brain vessel changes have never been documented in this syndrome.MethodsIn the present work, histological and ultrastructural analyses of brain capillaries from wild type and ryr1 mutated pigs were conducted to investigate the potential impairment of pericytes, in this pathology. In addition, brain pericytes were isolated from the three porcine genotypes (wild-type NN pigs; Nn and nn pigs, bearing one or two (n) mutant ryr1/hal alleles, respectively), and tested in vitro for their influence on the permeability of BBB endothelial monolayers.ResultsEnlarged perivascular spaces were observed in ryr1-mutant samples, corresponding to a partial or total detachment of the astrocytic endfeet. These spaces were electron lucent and sometimes filled with lipid deposits and swollen astrocytic feet. At the ultrastructural level, brain pericytes did not seem to be affected because they showed regular morphology and characteristics, so we aimed to check their ability to maintain BBB properties in vitro. Our results indicated that pericytes from the three genotypes of pigs had differing influences on the BBB. Unlike pericytes from NN pigs, pericytes from Nn and nn pigs were not able to maintain low BBB permeability.ConclusionsElectron microscopy observations demonstrated brain capillary modifications in PSS condition, but no change in pericyte morphology. Results from in vitro experiments suggest that brain pericytes from ryr1 mutated pigs, even if they are not affected by this condition at the ultrastructural level, are not able to maintain BBB integrity in comparison with pericytes from wild-type animals.

A defect in dystrophin causes a novel porcine stress syndrome

BackgroundLosses of slaughter-weight pigs due to transport stress are both welfare and economic concerns to pork producers. Historically, the HAL-1843 mutation in ryanodine receptor 1 was considered responsible for most of the losses; however, DNA testing has effectively eliminated this mutation from commercial herds. We identified two sibling barrows in the USMARC swine herd that died from apparent symptoms of a stress syndrome after transport at 12 weeks of age. The symptoms included open-mouth breathing, skin discoloration, vocalization and loss of mobility.ResultsWe repeated the original mating along with sire-daughter matings to produce additional offspring. At 8 weeks of age, heart rate and electrocardiographs (ECG) were monitored during isoflurane anesthesia challenge (3% for 3 min). Four males from the original sire-dam mating and two males from a sire-daughter mating died after one minute of anesthesia. Animals from additional litters were identified as having a stress response, sometimes resulting in death, during regular processing and weighing. Affected animals had elevated plasma creatine phosphokinase (CPK) levels before and immediately after isoflurane challenge and cardiac arrhythmias. A pedigree containing 250 pigs, including 49 affected animals, was genotyped with the Illumina PorcineSNP60 Beadchip and only one chromosomal region, SSCX at 25.1-27.7 Mb over the dystrophin gene (DMD), was significantly associated with the syndrome. An arginine to tryptophan (R1958W) polymorphism in exon 41 of DMD was the most significant marker associated with stress susceptibility. Immunoblots of affected heart and skeletal muscle showed a dramatic reduction of dystrophin protein and histopathology of affected hearts indicated muscle fiber degeneration.ConclusionsA novel stress syndrome was characterized in pigs and the causative genetic factor most likely resides within DMD that results in less dystrophin protein and cardiac abnormalities that can lead to death under stressful conditions. The identification of predictive markers will allow us to determine the prevalence of this disease in commercial swine populations. This defect also provides a unique biomedical model for human cardiomyopathy associated with muscular dystrophy that may be superior to those available because of the similarities in anatomy and physiology and allow advances in gene therapies for human disease.

Nonanesthetic Malignant Hyperthermia

Nonanesthetic Malignant Hyperthermia

An improved method for characterization of the mutation associated to porcine stress syndrome by PCR amplification followed by restriction analysis

A mutation in the gene coding for the ryanodine receptor 1 (RYR1), also known as halothane (hal) gene or swine stress gene, is associated to the porcine stress syndrome (PSS). Detection of the mutation is normally accomplished by PCR amplification of an 81bp fragment of the hal gene, followed by digestion with the HhaI restriction endonuclease. Wild-type allele (N) is cut in two fragments, whereas the mutant allele (n) is not digested by the restriction enzyme. Electrophoresis of the digested DNA on agarose gel and ethidium bromide staining allows the reading of the result. The correct interpretation is difficult due to the small size of the DNA fragments. In this study we designed a new set of primers for amplification of a 144bp fragment that facilitates the reading of the result. In addition, we optimized the PCR reaction to allow amplification from a single hair bulb, added directly into the PCR mix without previous treatment. This improved method was used to genotype 165 sows and boars used in a breeding program. Forty-nine percent of the animals had the NN genotype, whereas 50% were Nn and only 1% was nn.

Reduced Threshold for Luminal Ca2+ Activation of RyR1 Underlies a Causal Mechanism of Porcine Malignant Hyperthermia

Naturally occurring mutations in the skeletal muscle Ca(2+) release channel/ryanodine receptor RyR1 are linked to malignant hyperthermia (MH), a life-threatening complication of general anesthesia. Although it has long been recognized that MH results from uncontrolled or spontaneous Ca(2+) release from the sarcoplasmic reticulum, how MH RyR1 mutations render the sarcoplasmic reticulum susceptible to volatile anesthetic-induced spontaneous Ca(2+) release is unclear. Here we investigated the impact of the porcine MH mutation, R615C, the human equivalent of which also causes MH, on the intrinsic properties of the RyR1 channel and the propensity for spontaneous Ca(2+) release during store Ca(2+) overload, a process we refer to as store overload-induced Ca(2+) release (SOICR). Single channel analyses revealed that the R615C mutation markedly enhanced the luminal Ca(2+) activation of RyR1. Moreover, HEK293 cells expressing the R615C mutant displayed a reduced threshold for SOICR compared with cells expressing wild type RyR1. Furthermore, the MH-triggering agent, halothane, potentiated the response of RyR1 to luminal Ca(2+) and SOICR. Conversely, dantrolene, an effective treatment for MH, suppressed SOICR in HEK293 cells expressing the R615C mutant, but not in cells expressing an RyR2 mutant. These data suggest that the R615C mutation confers MH susceptibility by reducing the threshold for luminal Ca(2+) activation and SOICR, whereas volatile anesthetics trigger MH by further reducing the threshold, and dantrolene suppresses MH by increasing the SOICR threshold. Together, our data support a view in which altered luminal Ca(2+) regulation of RyR1 represents a primary causal mechanism of MH.