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Chang L, Gardner L, House C, Daly C, Allsopp A, Roiz de Sa D, Shaw MA, Hopkins PM. Comparison of Transcriptomic Changes in Survivors of Exertional Heat Illness with Malignant Hyperthermia Susceptible Patients. Int J Mol Sci 2023; 24:16124. [PMID: 38003313 PMCID: PMC10671540 DOI: 10.3390/ijms242216124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/02/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
Exertional heat illness (EHI) is an occupational health hazard for athletes and military personnel-characterised by the inability to thermoregulate during exercise. The ability to thermoregulate can be studied using a standardised heat tolerance test (HTT) developed by The Institute of Naval Medicine. In this study, we investigated whole blood gene expression (at baseline, 2 h post-HTT and 24 h post-HTT) in male subjects with either a history of EHI or known susceptibility to malignant hyperthermia (MHS): a pharmacogenetic condition with similar clinical phenotype. Compared to healthy controls at baseline, 291 genes were differentially expressed in the EHI cohort, with functional enrichment in inflammatory response genes (up to a four-fold increase). In contrast, the MHS cohort featured 1019 differentially expressed genes with significant down-regulation of genes associated with oxidative phosphorylation (OXPHOS). A number of differentially expressed genes in the inflammation and OXPHOS pathways overlapped between the EHI and MHS subjects, indicating a common underlying pathophysiology. Transcriptome profiles between subjects who passed and failed the HTT (based on whether they achieved a plateau in core temperature or not, respectively) were not discernable at baseline, and HTT was shown to elevate inflammatory response gene expression across all clinical phenotypes.
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Affiliation(s)
- Leon Chang
- Leeds Institute of Medical Research at St James’s, University of Leeds, Leeds LS9 7TF, UK; (L.C.); (M.-A.S.)
| | - Lois Gardner
- Leeds Institute of Medical Research at St James’s, University of Leeds, Leeds LS9 7TF, UK; (L.C.); (M.-A.S.)
| | - Carol House
- Survival and Thermal Medicine Department, Institute of Naval Medicine, Alverstoke, Hampshire PO12 2DL, UK
| | - Catherine Daly
- Malignant Hyperthermia Unit, St James’s University Hospital, Leeds LS9 7TF, UK;
| | - Adrian Allsopp
- Survival and Thermal Medicine Department, Institute of Naval Medicine, Alverstoke, Hampshire PO12 2DL, UK
| | - Daniel Roiz de Sa
- Survival and Thermal Medicine Department, Institute of Naval Medicine, Alverstoke, Hampshire PO12 2DL, UK
| | - Marie-Anne Shaw
- Leeds Institute of Medical Research at St James’s, University of Leeds, Leeds LS9 7TF, UK; (L.C.); (M.-A.S.)
| | - Philip M. Hopkins
- Leeds Institute of Medical Research at St James’s, University of Leeds, Leeds LS9 7TF, UK; (L.C.); (M.-A.S.)
- Malignant Hyperthermia Unit, St James’s University Hospital, Leeds LS9 7TF, UK;
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Frassanito L, Sbaraglia F, Piersanti A, Vassalli F, Lucente M, Filetici N, Zanfini BA, Catarci S, Draisci G. Real Evidence and Misconceptions about Malignant Hyperthermia in Children: A Narrative Review. J Clin Med 2023; 12:3869. [PMID: 37373564 PMCID: PMC10299046 DOI: 10.3390/jcm12123869] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 05/29/2023] [Accepted: 06/03/2023] [Indexed: 06/29/2023] Open
Abstract
Malignant hyperthermia is a rare but life-threatening pharmacogenetic disorder triggered by exposure to specific anesthetic agents. Although this occurrence could affect virtually any patient during the perioperative time, the pediatric population is particularly vulnerable, and it has a five-fold higher incidence in children compared to adults. In the last few decades, synergistic efforts among leading anesthesiology, pediatrics, and neurology associations have produced new evidence concerning the diagnostic pathway, avoiding unnecessary testing and limiting false diagnoses. However, a personalized approach and an effective prevention policy focused on clearly recognizing the high-risk population, defining perioperative trigger-free hospitalization, and rapid activation of supportive therapy should be improved. Based on epidemiological data, many national scientific societies have produced consistent guidelines, but many misconceptions are common among physicians and healthcare workers. This review shall consider all these aspects and summarize the most recent updates.
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Affiliation(s)
- Luciano Frassanito
- Department of Scienze dell’Emergenza, Anestesiologiche e della Rianimazione—IRCCS Fondazione Policlinico A. Gemelli, 00168 Rome, Italy; (F.S.); (A.P.); (M.L.); (N.F.); (B.A.Z.); (S.C.); (G.D.)
| | - Fabio Sbaraglia
- Department of Scienze dell’Emergenza, Anestesiologiche e della Rianimazione—IRCCS Fondazione Policlinico A. Gemelli, 00168 Rome, Italy; (F.S.); (A.P.); (M.L.); (N.F.); (B.A.Z.); (S.C.); (G.D.)
| | - Alessandra Piersanti
- Department of Scienze dell’Emergenza, Anestesiologiche e della Rianimazione—IRCCS Fondazione Policlinico A. Gemelli, 00168 Rome, Italy; (F.S.); (A.P.); (M.L.); (N.F.); (B.A.Z.); (S.C.); (G.D.)
| | - Francesco Vassalli
- Department of Critical Care and Perinatal Medicine, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Giannina Gaslini, 16147 Genoa, Italy;
| | - Monica Lucente
- Department of Scienze dell’Emergenza, Anestesiologiche e della Rianimazione—IRCCS Fondazione Policlinico A. Gemelli, 00168 Rome, Italy; (F.S.); (A.P.); (M.L.); (N.F.); (B.A.Z.); (S.C.); (G.D.)
| | - Nicoletta Filetici
- Department of Scienze dell’Emergenza, Anestesiologiche e della Rianimazione—IRCCS Fondazione Policlinico A. Gemelli, 00168 Rome, Italy; (F.S.); (A.P.); (M.L.); (N.F.); (B.A.Z.); (S.C.); (G.D.)
| | - Bruno Antonio Zanfini
- Department of Scienze dell’Emergenza, Anestesiologiche e della Rianimazione—IRCCS Fondazione Policlinico A. Gemelli, 00168 Rome, Italy; (F.S.); (A.P.); (M.L.); (N.F.); (B.A.Z.); (S.C.); (G.D.)
| | - Stefano Catarci
- Department of Scienze dell’Emergenza, Anestesiologiche e della Rianimazione—IRCCS Fondazione Policlinico A. Gemelli, 00168 Rome, Italy; (F.S.); (A.P.); (M.L.); (N.F.); (B.A.Z.); (S.C.); (G.D.)
| | - Gaetano Draisci
- Department of Scienze dell’Emergenza, Anestesiologiche e della Rianimazione—IRCCS Fondazione Policlinico A. Gemelli, 00168 Rome, Italy; (F.S.); (A.P.); (M.L.); (N.F.); (B.A.Z.); (S.C.); (G.D.)
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Tammineni ER, Figueroa L, Manno C, Varma D, Kraeva N, Ibarra CA, Klip A, Riazi S, Rios E. Muscle calcium stress cleaves junctophilin1, unleashing a gene regulatory program predicted to correct glucose dysregulation. eLife 2023; 12:e78874. [PMID: 36724092 PMCID: PMC9891728 DOI: 10.7554/elife.78874] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 01/11/2023] [Indexed: 02/02/2023] Open
Abstract
Calcium ion movements between cellular stores and the cytosol govern muscle contraction, the most energy-consuming function in mammals, which confers skeletal myofibers a pivotal role in glycemia regulation. Chronic myoplasmic calcium elevation ("calcium stress"), found in malignant hyperthermia-susceptible (MHS) patients and multiple myopathies, has been suggested to underlie the progression from hyperglycemia to insulin resistance. What drives such progression remains elusive. We find that muscle cells derived from MHS patients have increased content of an activated fragment of GSK3β - a specialized kinase that inhibits glycogen synthase, impairing glucose utilization and delineating a path to hyperglycemia. We also find decreased content of junctophilin1, an essential structural protein that colocalizes in the couplon with the voltage-sensing CaV1.1, the calcium channel RyR1 and calpain1, accompanied by an increase in a 44 kDa junctophilin1 fragment (JPh44) that moves into nuclei. We trace these changes to activated proteolysis by calpain1, secondary to increased myoplasmic calcium. We demonstrate that a JPh44-like construct induces transcriptional changes predictive of increased glucose utilization in myoblasts, including less transcription and translation of GSK3β and decreased transcription of proteins that reduce utilization of glucose. These effects reveal a stress-adaptive response, mediated by the novel regulator of transcription JPh44.
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Affiliation(s)
- Eshwar R Tammineni
- Department of Physiology and Biophysics, Rush UniversityChicagoUnited States
| | - Lourdes Figueroa
- Department of Physiology and Biophysics, Rush UniversityChicagoUnited States
| | - Carlo Manno
- Department of Physiology and Biophysics, Rush UniversityChicagoUnited States
| | - Disha Varma
- Department of Internal Medicine, Division of Nephrology, Rush UniversityChicagoUnited States
| | - Natalia Kraeva
- Department of Anesthesia & Pain Management, University of TorontoTorontoCanada
| | - Carlos A Ibarra
- Department of Anesthesia & Pain Management, University of TorontoTorontoCanada
| | - Amira Klip
- Cell Biology Program, The Hospital for Sick ChildrenTorontoCanada
| | - Sheila Riazi
- Department of Anesthesia & Pain Management, University of TorontoTorontoCanada
| | - Eduardo Rios
- Department of Physiology and Biophysics, Rush UniversityChicagoUnited States
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Malignant Hyperthermia in PICU—From Diagnosis to Treatment in the Light of Up-to-Date Knowledge. CHILDREN 2022; 9:children9111692. [DOI: 10.3390/children9111692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/04/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022]
Abstract
Malignant Hyperthermia (MH) is a rare, hereditary, life-threatening disease triggered by volatile anesthetics and succinylcholine. Rarely, MH can occur after non-pharmacological triggers too. MH was detected more often in children and young adults, which makes this topic very important for every pediatric specialist, both anesthesiologists and intensivists. MH crisis is a life-threatening severe hypermetabolic whole-body reaction. Triggers of MH are used in pediatric intensive care unit (PICU) as well, volatile anesthetics in difficult sedation, status asthmaticus or epilepticus, and succinylcholine still sometimes in airway management. Recrudescence or delayed onset of MH crisis hours after anesthesia was previously described. MH can also be a cause of rhabdomyolysis and hyperpyrexia in the PICU. In addition, patients with neuromuscular diseases are often admitted to PICU and they might be at risk for MH. The most typical symptoms of MH are hypercapnia, tachycardia, hyperthermia, and muscle rigidity. Thinking of the MH as the possible cause of deterioration of a patient’s clinical condition is the key to early diagnosis and treatment. The sooner the correct treatment is commenced, the better patient´s outcome. This narrative review article aims to summarize current knowledge and guidelines about recognition, treatment, and further management of MH in PICU.
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Protasi F, Girolami B, Serano M, Pietrangelo L, Paolini C. Ablation of Calsequestrin-1, Ca 2+ unbalance, and susceptibility to heat stroke. Front Physiol 2022; 13:1033300. [PMID: 36311237 PMCID: PMC9598425 DOI: 10.3389/fphys.2022.1033300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/20/2022] [Indexed: 12/05/2022] Open
Abstract
Introduction: Ca2+ levels in adult skeletal muscle fibers are mainly controlled by excitation-contraction (EC) coupling, a mechanism that translates action potentials in release of Ca2+ from the sarcoplasmic reticulum (SR) release channels, i.e. the ryanodine receptors type-1 (RyR1). Calsequestrin (Casq) is a protein that binds large amounts of Ca2+ in the lumen of the SR terminal cisternae, near sites of Ca2+ release. There is general agreement that Casq is not only important for the SR ability to store Ca2+, but also for modulating the opening probability of the RyR Ca2+ release channels. The initial studies: About 20 years ago we generated a mouse model lacking Casq1 (Casq1-null mice), the isoform predominantly expressed in adult fast twitch skeletal muscle. While the knockout was not lethal as expected, lack of Casq1 caused a striking remodeling of membranes of SR and of transverse tubules (TTs), and mitochondrial damage. Functionally, CASQ1-knockout resulted in reduced SR Ca2+ content, smaller Ca2+ transients, and severe SR depletion during repetitive stimulation. The myopathic phenotype of Casq1-null mice: After the initial studies, we discovered that Casq1-null mice were prone to sudden death when exposed to halogenated anaesthetics, heat and even strenuous exercise. These syndromes are similar to human malignant hyperthermia susceptibility (MHS) and environmental-exertional heat stroke (HS). We learned that mechanisms underlying these syndromes involved excessive SR Ca2+ leak and excessive production of oxidative species: indeed, mortality and mitochondrial damage were significantly prevented by administration of antioxidants and reduction of oxidative stress. Though, how Casq1-null mice could survive without the most important SR Ca2+ binding protein was a puzzling issue that was not solved. Unravelling the mystery: The mystery was finally solved in 2020, when we discovered that in Casq1-null mice the SR undergoes adaptations that result in constitutively active store-operated Ca2+ entry (SOCE). SOCE is a mechanism that allows skeletal fibers to use external Ca2+ when SR stores are depleted. The post-natal compensatory mechanism that allows Casq1-null mice to survive involves the assembly of new SR-TT junctions (named Ca2+ entry units) containing Stim1 and Orai1, the two proteins that mediate SOCE.
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Affiliation(s)
- Feliciano Protasi
- Center for Advanced Studies and Technology, University G. d’Annunzio of Chieti-Pescara, Chieti, Italy
- Department of Medicine and Aging Sciences, University G. d’Annunzio of Chieti-Pescara, Chieti, Italy
| | - Barbara Girolami
- Center for Advanced Studies and Technology, University G. d’Annunzio of Chieti-Pescara, Chieti, Italy
- Department of Medicine and Aging Sciences, University G. d’Annunzio of Chieti-Pescara, Chieti, Italy
| | - Matteo Serano
- Center for Advanced Studies and Technology, University G. d’Annunzio of Chieti-Pescara, Chieti, Italy
- Department of Medicine and Aging Sciences, University G. d’Annunzio of Chieti-Pescara, Chieti, Italy
| | - Laura Pietrangelo
- Center for Advanced Studies and Technology, University G. d’Annunzio of Chieti-Pescara, Chieti, Italy
- Department of Medicine and Aging Sciences, University G. d’Annunzio of Chieti-Pescara, Chieti, Italy
| | - Cecilia Paolini
- Center for Advanced Studies and Technology, University G. d’Annunzio of Chieti-Pescara, Chieti, Italy
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d’Annunzio of Chieti-Pescara, Chieti, Italy
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Serano M, Pietrangelo L, Paolini C, Guarnier FA, Protasi F. Oxygen Consumption and Basal Metabolic Rate as Markers of Susceptibility to Malignant Hyperthermia and Heat Stroke. Cells 2022; 11:2468. [PMID: 36010545 PMCID: PMC9406760 DOI: 10.3390/cells11162468] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/04/2022] [Accepted: 08/06/2022] [Indexed: 12/28/2022] Open
Abstract
Calsequestrin 1 (CASQ1) and Ryanodine receptor 1 (RYR1) are two of the main players in excitation-contraction (EC) coupling. CASQ1-knockout mice and mice carrying a mutation in RYR1 (Y522S) linked to human malignant hyperthermia susceptibility (MHS) both suffer lethal hypermetabolic episodes when exposed to halothane (MHS crises) and to environmental heat (heat stroke, HS). The phenotype of Y522S is more severe than that of CASQ1-null mice. As MHS and HS are hypermetabolic responses, we studied the metabolism of adult CASQ1-null and Y522S mice using wild-type (WT) mice as controls. We found that CASQ1-null and Y522S mice have increased food consumption and higher core temperature at rest. By indirect calorimetry, we then verified that CASQ1-null and Y522S mice show an increased oxygen consumption and a lower respiratory quotient (RQ). The accelerated metabolism of CASQ1-null and Y522S mice was also accompanied with a reduction in body fat. Moreover, both mouse models displayed increased oxygen consumption and a higher core temperature during heat stress. The results collected suggest that metabolic rate, oxygen consumption, and body temperature at rest, all more elevated in Y522S than in CASQ1-null mice, could possibly be used as predictors of the level of susceptibility to hyperthermic crises of mice (and possibly humans).
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Affiliation(s)
- Matteo Serano
- CAST, Center for Advanced Studies and Technology, University G. d’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
- DMSI, Department of Medicine and Aging Sciences, University G. d’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Laura Pietrangelo
- CAST, Center for Advanced Studies and Technology, University G. d’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
- DMSI, Department of Medicine and Aging Sciences, University G. d’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Cecilia Paolini
- CAST, Center for Advanced Studies and Technology, University G. d’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
- DNICS, Department of Neuroscience and Clinical Sciences, University G. d’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Flavia A. Guarnier
- Department of General Pathology, Londrina State University, Londrina 86057-970, Brazil
| | - Feliciano Protasi
- CAST, Center for Advanced Studies and Technology, University G. d’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
- DMSI, Department of Medicine and Aging Sciences, University G. d’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
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Bin X, Wang B, Tang Z. Malignant Hyperthermia: A Killer If Ignored. J Perianesth Nurs 2022; 37:435-444. [DOI: 10.1016/j.jopan.2021.08.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 08/23/2021] [Accepted: 08/26/2021] [Indexed: 11/26/2022]
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Store-Operated Ca 2+ Entry in Skeletal Muscle Contributes to the Increase in Body Temperature during Exertional Stress. Int J Mol Sci 2022; 23:ijms23073772. [PMID: 35409132 PMCID: PMC8998704 DOI: 10.3390/ijms23073772] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/26/2022] [Accepted: 03/26/2022] [Indexed: 12/15/2022] Open
Abstract
Exertional heat stroke (HS) is a hyperthermic crisis triggered by an excessive accumulation of Ca2+ in skeletal muscle fibers. We demonstrated that exercise leads to the formation of calcium entry units (CEUs), which are intracellular junctions that reduce muscle fatigue by promoting the recovery of extracellular Ca2+ via store-operated Ca2+ entry (SOCE). Here, we tested the hypothesis that exercise-induced assembly of CEUs may increase the risk of HS when physical activity is performed in adverse environmental conditions (high temperature and humidity). Adult mice were: (a) first, divided into three experimental groups: control, trained-1 month (voluntary running in wheel cages), and acutely exercised-1 h (incremental treadmill run); and (b) then subjected to an exertional stress (ES) protocol, a treadmill run in an environmental chamber at 34 °C and 40% humidity. The internal temperature of the mice at the end of the ES was higher in both pre-exercised groups. During an ES ex-vivo protocol, extensor digitorum longus(EDL) muscles from the trained-1 month and exercised-1 h mice generated greater basal tension than in the control and were those that contained a greater number of CEUs, assessed by electron microscopy. The data collected suggest that the entry of Ca2+ from extracellular space via CEUs could contribute to exertional HS when exercise is performed in adverse environmental conditions.
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van den Bersselaar LR, Riazi S, Snoeck M, Jungbluth H, Voermans NC. 259th ENMC international workshop: Anaesthesia and neuromuscular disorders 11 December, 2020 and 28-29 May, 2021. Neuromuscul Disord 2021; 32:86-97. [PMID: 34916120 DOI: 10.1016/j.nmd.2021.11.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 11/09/2021] [Accepted: 11/12/2021] [Indexed: 02/07/2023]
Affiliation(s)
- L R van den Bersselaar
- Department of Anaesthesiology, Malignant Hyperthermia Investigation Unit, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands; Department of Neurology, Radboud University Medical Center, Reinier Postlaan 4, P.O. Box 9101, 6500 HB, Nijmegen 6525 GC, the Netherlands
| | - S Riazi
- Department of Anesthesiology and Pain Medicine, Malignant Hyperthermia Investigation Unit, University Health Network, University of Toronto, Toronto, Canada
| | - Mmj Snoeck
- Department of Anaesthesiology, Malignant Hyperthermia Investigation Unit, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands
| | - H Jungbluth
- Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, United Kingdom; Randall Centre for Cell and Molecular Biophysics, Muscle Signalling Section, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - N C Voermans
- Department of Neurology, Radboud University Medical Center, Reinier Postlaan 4, P.O. Box 9101, 6500 HB, Nijmegen 6525 GC, the Netherlands.
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Overlapping Mechanisms of Exertional Heat Stroke and Malignant Hyperthermia: Evidence vs. Conjecture. Sports Med 2020; 50:1581-1592. [DOI: 10.1007/s40279-020-01318-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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Abstract
Malignant hyperthermia (MH) is a rare but potentially lethal skeletal muscle disorder affecting calcium release channels. It is inherited in a mendelian autosomal dominant pattern with variable penetration. The initial clinical manifestations are of a hypermetabolic state with increased CO2 production, respiratory acidosis, increased temperature, and increased oxygen demands. If diagnosed late, MH progresses to multi-organ system failure and death. Current data suggest that mortality has improved to less than 5%. The gold standard for ruling out MH is the contracture test. Genetic testing is also available. MH-susceptible individuals should be clearly identified for safe administration of future anesthetics.
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Affiliation(s)
- Herodotos Ellinas
- Department of Anesthesiology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA.
| | - Meredith A Albrecht
- Department of Anesthesiology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA
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12
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Gardner L, Miller DM, Daly C, Gupta PK, House C, Roiz de Sa D, Shaw MA, Hopkins PM. Investigating the genetic susceptibility to exertional heat illness. J Med Genet 2020; 57:531-541. [DOI: 10.1136/jmedgenet-2019-106461] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 11/25/2019] [Accepted: 12/21/2019] [Indexed: 12/16/2022]
Abstract
BackgroundWe aimed to identify rare (minor allele frequency ≤1%), potentially pathogenic non-synonymous variants in a well-characterised cohort with a clinical history of exertional heat illness (EHI) or exertional rhabdomyolysis (ER). The genetic link between malignant hyperthermia (MH) and EHI was investigated due to their phenotypic overlap.MethodsThe coding regions of 38 genes relating to skeletal muscle calcium homeostasis or exercise intolerance were sequenced in 64 patients (mostly military personnel) with a history of EHI, or ER and who were phenotyped using skeletal muscle in vitro contracture tests. We assessed the pathogenicity of variants using prevalence data, in silico analysis, phenotype and segregation evidence and by review of the literature.ResultsWe found 51 non-polymorphic, potentially pathogenic variants in 20 genes in 38 patients. Our data indicate that RYR1 p.T3711M (previously shown to be likely pathogenic for MH susceptibility) and RYR1 p.I3253T are likely pathogenic for EHI. PYGM p.A193S was found in 3 patients with EHI, which is significantly greater than the control prevalence (p=0.000025). We report the second case of EHI in which a missense variant at CACNA1S p.R498 has been found. Combinations of rare variants in the same or different genes are implicated in EHI.ConclusionWe confirm a role of RYR1 in the heritability of EHI as well as ER but highlight the likely genetic heterogeneity of these complex conditions. We propose defects, or combinations of defects, in skeletal muscle calcium homeostasis, oxidative metabolism and membrane excitability are associated with EHI.
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Laitano O, Leon LR, Roberts WO, Sawka MN. Controversies in exertional heat stroke diagnosis, prevention, and treatment. J Appl Physiol (1985) 2019; 127:1338-1348. [DOI: 10.1152/japplphysiol.00452.2019] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
During the past several decades, the incidence of exertional heat stroke (EHS) has increased dramatically. Despite an improved understanding of this syndrome, numerous controversies still exist within the scientific and health professions regarding diagnosis, pathophysiology, risk factors, treatment, and return to physical activity. This review examines the following eight controversies: 1) reliance on core temperature for diagnosing and assessing severity of EHS; 2) hypothalamic damage induces heat stroke and this mediates “thermoregulatory failure” during the immediate recovery period; 3) EHS is a predictable condition primarily resulting from overwhelming heat stress; 4) heat-induced endotoxemia mediates systemic inflammatory response syndrome in all EHS cases; 5) nonsteroidal anti-inflammatory drugs for EHS prevention; 6) EHS shares similar mechanisms with malignant hyperthermia; 7) cooling to a specific body core temperature during treatment for EHS; and 8) return to physical activity based on physiological responses to a single-exercise heat tolerance test. In this review, we present and discuss the origins and the evidence for each controversy and propose next steps to resolve the misconception.
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Affiliation(s)
- Orlando Laitano
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida
| | - Lisa R. Leon
- Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts
| | - William O. Roberts
- Department of Family Medicine and Community Health, University of Minnesota Twin Cities, Minneapolis, Minnesota
| | - Michael N. Sawka
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia
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Capacchione J. What More Can We Learn from Jordan McNair? Curr Sports Med Rep 2019; 18:161-162. [PMID: 31082887 DOI: 10.1249/jsr.0000000000000596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Affiliation(s)
- John Capacchione
- Department of Anesthesiology, University of Minnesota, Minneapolis, Minnesota; Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and Medical Corps United States Navy Reserve
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Thermoregulation and markers of muscle breakdown in malignant hyperthermia susceptible volunteers during an acute heat tolerance test. J Sci Med Sport 2019; 22:586-590. [DOI: 10.1016/j.jsams.2018.11.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 10/03/2018] [Accepted: 11/06/2018] [Indexed: 01/24/2023]
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Litman RS, Smith VI, Larach MG, Mayes L, Shukry M, Theroux MC, Watt S, Wong CA. Consensus Statement of the Malignant Hyperthermia Association of the United States on Unresolved Clinical Questions Concerning the Management of Patients With Malignant Hyperthermia. Anesth Analg 2019; 128:652-659. [DOI: 10.1213/ane.0000000000004039] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Aerobic Training Prevents Heatstrokes in Calsequestrin-1 Knockout Mice by Reducing Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:4652480. [PMID: 29849896 PMCID: PMC5903204 DOI: 10.1155/2018/4652480] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Revised: 02/01/2018] [Accepted: 02/21/2018] [Indexed: 01/06/2023]
Abstract
Calsequestrin-1 knockout (CASQ1-null) mice suffer lethal episodes when exposed to strenuous exercise and environmental heat, crises known as exertional/environmental heatstroke (EHS). We previously demonstrated that administration of exogenous antioxidants (N-acetylcysteine and trolox) reduces CASQ1-null mortality during exposure to heat. As aerobic training is known to boost endogenous antioxidant protection, we subjected CASQ1-null mice to treadmill running for 2 months at 60% of their maximal speed for 1 h, 5 times/week. When exposed to heat stress protocol (41°C/1 h), the mortality rate of CASQ1-null mice was significantly reduced compared to untrained animals (86% versus 16%). Protection from heatstrokes was accompanied by a reduced increase in core temperature during the stress protocol and by an increased threshold of response to caffeine of isolated extensor digitorum longus muscles during in vitro contracture test. At cellular and molecular levels, aerobic training (i) improved mitochondrial function while reducing their damage and (ii) lowered calpain activity and lipid peroxidation in membranes isolated from sarcoplasmic reticulum and mitochondria. Based on this evidence, we hypothesize that the protective effect of aerobic training is essentially mediated by a reduction in oxidative stress during exposure of CASQ1-null mice to adverse environmental conditions.
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Abstract
This article reviews advancements in the genetics of malignant hyperthermia, new technologies and approaches for its diagnosis, and the existing limitations of genetic testing for malignant hyperthermia. It also reviews the various RYR1-related disorders and phenotypes, such as myopathies, exertional rhabdomyolysis, and bleeding disorders, and examines the connection between these disorders and malignant hyperthermia.
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Nicoll BK, Ferreira C, Hopkins PM, Shaw MA, Hope IA. Aging Effects of Caenorhabditis elegans Ryanodine Receptor Variants Corresponding to Human Myopathic Mutations. G3 (BETHESDA, MD.) 2017; 7:1451-1461. [PMID: 28325813 PMCID: PMC5427508 DOI: 10.1534/g3.117.040535] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 03/07/2017] [Indexed: 12/31/2022]
Abstract
Delaying the decline in skeletal muscle function will be critical to better maintenance of an active lifestyle in old age. The skeletal muscle ryanodine receptor, the major intracellular membrane channel through which calcium ions pass to elicit muscle contraction, is central to calcium ion balance and is hypothesized to be a significant factor for age-related decline in muscle function. The nematode Caenorhabditis elegans is a key model system for the study of human aging, and strains were generated with modified C. elegans ryanodine receptors corresponding to human myopathic variants linked with malignant hyperthermia and related conditions. The altered response of these strains to pharmacological agents reflected results of human diagnostic tests for individuals with these pathogenic variants. Involvement of nerve cells in the C. elegans responses may relate to rare medical symptoms concerning the central nervous system that have been associated with ryanodine receptor variants. These single amino acid modifications in C. elegans also conferred a reduction in lifespan and an accelerated decline in muscle integrity with age, supporting the significance of ryanodine receptor function for human aging.
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Affiliation(s)
- Baines K Nicoll
- Leeds Institute of Biomedical and Clinical Sciences, St James's University Hospital, LS9 7TF, United Kingdom
- School of Biology, Faculty of Biological Sciences, University of Leeds, LS2 9JT, United Kingdom
| | - Célia Ferreira
- School of Biology, Faculty of Biological Sciences, University of Leeds, LS2 9JT, United Kingdom
| | - Philip M Hopkins
- Leeds Institute of Biomedical and Clinical Sciences, St James's University Hospital, LS9 7TF, United Kingdom
| | - Marie-Anne Shaw
- Leeds Institute of Biomedical and Clinical Sciences, St James's University Hospital, LS9 7TF, United Kingdom
| | - Ian A Hope
- School of Biology, Faculty of Biological Sciences, University of Leeds, LS2 9JT, United Kingdom
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Michelucci A, Paolini C, Boncompagni S, Canato M, Reggiani C, Protasi F. Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia. FASEB J 2017; 31:3649-3662. [PMID: 28465322 DOI: 10.1096/fj.201601292r] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 04/17/2017] [Indexed: 12/26/2022]
Abstract
In humans, hyperthermic episodes can be triggered by halogenated anesthetics [malignant hyperthermia (MH) susceptibility] and by high temperature [environmental heat stroke (HS)]. Correlation between MH susceptibility and HS is supported by extensive work in mouse models that carry a mutation in ryanodine receptor type-1 (RYR1Y522S/WT) and calsequestrin-1 knockout (CASQ1-null), 2 proteins that control Ca2+ release in skeletal muscle. As overheating episodes in humans have also been described during exertion, here we subjected RYR1Y522S/WT and CASQ1-null mice to an exertional-stress protocol (incremental running on a treadmill at 34°C and 40% humidity). The mortality rate was 80 and 78.6% in RYR1Y522S/WT and CASQ1-null mice, respectively, vs. 0% in wild-type mice. Lethal crises were characterized by hyperthermia and rhabdomyolysis, classic features of MH episodes. Of importance, pretreatment with azumolene, an analog of the drug used in humans to treat MH crises, reduced mortality to 0 and 12.5% in RYR1Y522S/WT and CASQ1-null mice, respectively, thanks to a striking reduction of hyperthermia and rhabdomyolysis. At the molecular level, azumolene strongly prevented Ca2+-dependent activation of calpains and NF-κB by lowering myoplasmic Ca2+ concentration and nitro-oxidative stress, parameters that were elevated in RYR1Y522S/WT and CASQ1-null mice. These results suggest that common molecular mechanisms underlie MH crises and exertional HS in mice.-Michelucci, A., Paolini, C., Boncompagni, S., Canato, M., Reggiani, C., Protasi, F. Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia.
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Affiliation(s)
- Antonio Michelucci
- Center for Research on Ageing and Translational Medicine (CeSI-MeT), Department of Neuroscience, Imaging, and Clinical Sciences (DNICS), Università degli Studi G. d'Annunzio, Chieti, Italy
| | - Cecilia Paolini
- Center for Research on Ageing and Translational Medicine (CeSI-MeT), Department of Neuroscience, Imaging, and Clinical Sciences (DNICS), Università degli Studi G. d'Annunzio, Chieti, Italy
| | - Simona Boncompagni
- Center for Research on Ageing and Translational Medicine (CeSI-MeT), Department of Neuroscience, Imaging, and Clinical Sciences (DNICS), Università degli Studi G. d'Annunzio, Chieti, Italy
| | - Marta Canato
- Department of Biomedical Sciences, University of Padova, Padua, Italy
| | - Carlo Reggiani
- Department of Biomedical Sciences, University of Padova, Padua, Italy
| | - Feliciano Protasi
- Center for Research on Ageing and Translational Medicine (CeSI-MeT), Department of Neuroscience, Imaging, and Clinical Sciences (DNICS), Università degli Studi G. d'Annunzio, Chieti, Italy; .,Department of Medicine and Aging Science, University G. d' Annunzio of Chieti, Chieti, Italy
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Heytens K, De Bleecker J, Verbrugghe W, Baets J, Heytens L. Exertional rhabdomyolysis and heat stroke: Beware of volatile anesthetic sedation. World J Crit Care Med 2017; 6:21-27. [PMID: 28224104 PMCID: PMC5295166 DOI: 10.5492/wjccm.v6.i1.21] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 09/27/2016] [Accepted: 11/17/2016] [Indexed: 02/06/2023] Open
Abstract
In view of the enormous popularity of mass sporting events such as half-marathons, the number of patients with exertional rhabdomyolysis or exercise-induced heat stroke admitted to intensive care units (ICUs) has increased over the last decade. Because these patients have been reported to be at risk for malignant hyperthermia during general anesthesia, the intensive care community should bear in mind that the same risk of life-threatening rhabdomyolysis is present when these patients are admitted to an ICU, and volatile anesthetic sedation is chosen as the sedative technique. As illustrated by the three case studies we elaborate upon, a thorough diagnostic work-up is needed to clarify the subsequent risk of strenuous exercise, and the anesthetic exposure to volatile agents in these patients and their families. Other contraindications for the use of volatile intensive care sedation consist of known malignant hyperthermia susceptibility, congenital myopathies, Duchenne muscular dystrophy, and intracranial hypertension.
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Voermans NC, Snoeck M, Jungbluth H. RYR1-related rhabdomyolysis: A common but probably underdiagnosed manifestation of skeletal muscle ryanodine receptor dysfunction. Rev Neurol (Paris) 2016; 172:546-558. [PMID: 27663056 DOI: 10.1016/j.neurol.2016.07.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 07/29/2016] [Indexed: 01/04/2023]
Abstract
Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are associated with a wide spectrum of inherited myopathies presenting throughout life. Malignant hyperthermia susceptibility (MHS)-related RYR1 mutations have emerged as a common cause of exertional rhabdomyolysis, accounting for up to 30% of rhabdomyolysis episodes in otherwise healthy individuals. Common triggers are exercise and heat and, less frequently, viral infections, alcohol and drugs. Most subjects are normally strong and have no personal or family history of malignant hyperthermia. Heat intolerance and cold-induced muscle stiffness may be a feature. Recognition of this (probably not uncommon) rhabdomyolysis cause is vital for effective counselling, to identify potentially malignant hyperthermia-susceptible individuals and to adapt training regimes. Studies in various animal models provide insights regarding possible pathophysiological mechanisms and offer therapeutic perspectives.
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Affiliation(s)
- N C Voermans
- Department of Neurology, Radboud University Medical Centre, R. Postlaan 4 (route 935), P.O. Box 9101, 6500 Nijmegen (935), The Netherlands.
| | - M Snoeck
- Department of Anaesthesia, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands
| | - H Jungbluth
- Department of Paediatric Neurology, Neuromuscular Service, Evelina Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, UK; Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section, London, UK; Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK
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23
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In Reply. Anesthesiology 2016; 124:511. [DOI: 10.1097/aln.0000000000000980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Hopkins P, Rüffert H, Snoeck M, Girard T, Glahn K, Ellis F, Müller C, Urwyler A. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth 2015; 115:531-9. [DOI: 10.1093/bja/aev225] [Citation(s) in RCA: 133] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Michelucci A, Paolini C, Canato M, Wei-Lapierre L, Pietrangelo L, De Marco A, Reggiani C, Dirksen RT, Protasi F. Antioxidants protect calsequestrin-1 knockout mice from halothane- and heat-induced sudden death. Anesthesiology 2015; 123:603-17. [PMID: 26132720 PMCID: PMC4543432 DOI: 10.1097/aln.0000000000000748] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Mice lacking calsequestrin-1 (CASQ1-null), a Ca-binding protein that modulates the activity of Ca release in the skeletal muscle, exhibit lethal hypermetabolic episodes that resemble malignant hyperthermia in humans when exposed to halothane or heat stress. METHODS Because oxidative species may play a critical role in malignant hyperthermia crises, we treated CASQ1-null mice with two antioxidants, N-acetylcysteine (NAC, Sigma-Aldrich, Italy; provided ad libitum in drinking water) and (±)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox, Sigma-Aldrich; administered by intraperitoneal injection), before exposure to halothane (2%, 1 h) or heat (41°C, 1 h). RESULTS NAC and Trolox significantly protected CASQ1-null mice from lethal episodes, with mortality being 79% (n = 14), 25% (n = 16), and 20% (n = 5) during halothane exposure and 86% (n = 21), 29% (n = 21), and 33% (n = 6) during heat stress in untreated, NAC-treated, and Trolox-treated mice, respectively. During heat challenge, an increase in core temperature in CASQ1-null mice (42.3° ± 0.1°C, n=10) was significantly reduced by both NAC and Trolox (40.6° ± 0.3°C, n = 6 and 40.5° ± 0.2°C, n = 6). NAC treatment of CASQ1-null muscles/mice normalized caffeine sensitivity during in vitro contracture tests, Ca transients in single fibers, and significantly reduced the percentage of fibers undergoing rhabdomyolysis (37.6 ± 2.5%, 38/101 fibers in 3 mice; 11.6 ± 1.1%, 21/186 fibers in 5 mice). The protective effect of antioxidant treatment likely resulted from mitigation of oxidative stress, because NAC reduced mitochondrial superoxide production, superoxide dismutase type-1 expression, and 3-nitrotyrosine expression, and increased both reduced glutathione and reduced glutathione/oxidized glutathione ratio. CONCLUSION These studies provide a deeper understanding of the mechanisms that underlie hyperthermic crises in CASQ1-deficient muscle and demonstrate that antioxidant pretreatment may prevent them.
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Affiliation(s)
- Antonio Michelucci
- Postdoctoral Fellow, CeSI - Center for Research on Ageing & DNICS – Department of Neuroscience, Imaging and Clinical Sciences, University G. d’Annunzio of Chieti, I-66100 Chieti, Italy
| | - Cecilia Paolini
- Assistant Professor, CeSI - Center for Research on Ageing & DNICS – Department of Neuroscience, Imaging and Clinical Sciences, University G. d’Annunzio of Chieti, I-66100 Chieti, Italy
| | - Marta Canato
- Research Assistant, Department of Biomedical Sciences, University of Padova, I-35131 Italy
| | - Lan Wei-Lapierre
- Research Assistant Professor, Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642
| | - Laura Pietrangelo
- Postdoctoral Fellow, CeSI - Center for Research on Ageing & DNICS – Department of Neuroscience, Imaging and Clinical Sciences, University G. d’Annunzio of Chieti, I-66100 Chieti, Italy
| | - Alessandro De Marco
- Postdoctoral fellow, CeSI - Center for Research on Ageing & DNICS – Department of Neuroscience, Imaging and Clinical Sciences, University G. d’Annunzio of Chieti, I-66100 Chieti, Italy
| | - Carlo Reggiani
- Professor, Department of Biomedical Sciences, University of Padova, I-35131 Italy
| | - Robert T. Dirksen
- Professor, Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642
| | - Feliciano Protasi
- Professor, CeSI - Center for Research on Ageing & DNICS – Department of Neuroscience, Imaging and Clinical Sciences, University G. d’Annunzio of Chieti, I-66100 Chieti, Italy
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Sagui E, Montigon C, Abriat A, Jouvion A, Duron-Martinaud S, Canini F, Zagnoli F, Bendahan D, Figarella-Branger D, Brégigeon M, Brosset C. Is there a link between exertional heat stroke and susceptibility to malignant hyperthermia? PLoS One 2015; 10:e0135496. [PMID: 26258863 PMCID: PMC4530942 DOI: 10.1371/journal.pone.0135496] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Accepted: 07/22/2015] [Indexed: 11/18/2022] Open
Abstract
Objective The identification of a predisposition toward malignant hyperthermia (MH) as a risk factor for exertional heat stroke (EHS) remains a matter of debate. Such a predisposition indicates a causal role for MH susceptibility (MHS) after EHS in certain national recommendations and has led to the use of an in vitro contracture test (IVCT) to identify the MHS trait in selected or unselected EHS patients. The aim of this study was to determine whether the MHS trait is associated with EHS. Methods EHS subjects in the French Armed Forces were routinely examined for MHS after experiencing an EHS episode. This retrospective study compared the features of IVCT-diagnosed MHS (iMHS) EHS subjects with those of MH-normal EHS patients and MH patients during the 2004–2010 period. MHS status was assessed using the European protocol. Results During the study period, 466 subjects (median age 25 years; 31 women) underwent MHS status investigation following an EHS episode. None of the subjects reported previous MH events. An IVCT was performed in 454 cases and was diagnostic of MHS in 45.6% of the study population, of MH susceptibility to halothane in 18.5%, of MH susceptibility to caffeine in 9.9%, and of MH susceptibility to halothane and caffeine in 17.2%. There were no differences in the clinical features, biological features or outcomes of iMHS EHS subjects compared with those of MH-normal or caffeine or halothane MHS subjects without known prior EHS episode. The recurrence rate was 12.7% and was not associated with MH status or any clinical or biological features. iMHS EHS patients exhibited a significantly less informative IVCT response than MH patients. Conclusions The unexpected high prevalence of the MHS trait after EHS suggested a latent disturbance of calcium homeostasis that accounted for the positive IVCT results. This study did not determine whether EHS patients have an increased risk of MH, and it could not determine whether MH susceptibility is a risk factor for EHS.
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Affiliation(s)
- Emmanuel Sagui
- French Military Hospital Laveran, Marseille, France
- Val de Grâce Military School, Paris, France
- Unité mixte de recherche 7291, laboratoire de neurosciences cognitives, Aix Marseille University, Marseille, France
- * E-mail:
| | - Coline Montigon
- French Military Hospital Laveran, Marseille, France
- Val de Grâce Military School, Paris, France
| | | | | | | | - Frédéric Canini
- Val de Grâce Military School, Paris, France
- Armed Forces Biomedical Research Institute, Brétigny/Orge, France
| | - Fabien Zagnoli
- Val de Grâce Military School, Paris, France
- French Military Hospital Clermont-Tonnerre, Brest, France
| | - David Bendahan
- Unité mixte de recherché 7339, Center for Magnetic Resonance in Biology and Medicine, Aix Marseille University, Marseille, France
| | - Dominique Figarella-Branger
- Service d’anatomie pathologique et de neuropathologie, Timone hospital, assistance publique/hôpitaux de Marseille, Marseille, France
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Fiszer D, Shaw MA, Fisher NA, Carr IM, Gupta PK, Watkins EJ, de Sa DR, Kim JH, Hopkins PM. Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness. Anesthesiology 2015; 122:1033-46. [PMID: 25658027 PMCID: PMC4472733 DOI: 10.1097/aln.0000000000000610] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND Variants in RYR1 are associated with the majority of cases of malignant hyperthermia (MH), a form of heat illness pharmacogenetically triggered by general anesthetics, and they have also been associated with exertional heat illness (EHI). CACNA1S has also been implicated in MH. The authors applied a targeted next-generation sequencing approach to identify variants in RYR1 and CACNA1S in a cohort of unrelated patients diagnosed with MH susceptibility. They also provide the first comprehensive report of sequencing of these two genes in a cohort of survivors of EHI. METHODS DNA extracted from blood was genotyped using a "long" polymerase chain reaction technique, with sequencing on the Illumina GAII or MiSeq platforms (Illumina Inc., USA). Variants were assessed for pathogenicity using bioinformatic approaches. For further follow-up, DNA from additional family members and up to 211 MH normal and 556 MH-susceptible unrelated individuals was tested. RESULTS In 29 MH patients, the authors identified three pathogenic and four novel RYR1 variants, with a further five RYR1 variants previously reported in association with MH. Three novel RYR1 variants were found in the EHI cohort (n = 28) along with two more previously reported in association with MH. Two other variants were reported previously associated with centronuclear myopathy. The authors found one and three rare variants of unknown significance in CACNA1S in the MH and EHI cohorts, respectively. CONCLUSIONS Targeted next-generation sequencing proved efficient at identifying diagnostically useful and potentially implicated variants in RYR1 and CACNA1S in MH and EHI.
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Affiliation(s)
- Dorota Fiszer
- Leeds Institute of Biomedical & Clinical Sciences, School of Medicine, University of Leeds, United Kingdom
- Malignant Hyperthermia Investigation Unit, St. James’s University Hospital, Leeds, United Kingdom
| | - Marie-Anne Shaw
- Leeds Institute of Biomedical & Clinical Sciences, School of Medicine, University of Leeds, United Kingdom
- Malignant Hyperthermia Investigation Unit, St. James’s University Hospital, Leeds, United Kingdom
| | - Nickla A. Fisher
- Malignant Hyperthermia Investigation Unit, St. James’s University Hospital, Leeds, United Kingdom
| | - Ian M. Carr
- Leeds Institute of Biomedical & Clinical Sciences, School of Medicine, University of Leeds, United Kingdom
| | - Pawan K. Gupta
- Malignant Hyperthermia Investigation Unit, St. James’s University Hospital, Leeds, United Kingdom
| | - Elizabeth J. Watkins
- Malignant Hyperthermia Investigation Unit, St. James’s University Hospital, Leeds, United Kingdom
| | - Daniel Roiz de Sa
- Environmental Medicine and Science Division, Institute of Naval Medicine, Alverstoke, Hampshire, United Kingdom
| | - Jerry H. Kim
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington
| | - Philip M. Hopkins
- Leeds Institute of Biomedical & Clinical Sciences, School of Medicine, University of Leeds, United Kingdom
- Malignant Hyperthermia Investigation Unit, St. James’s University Hospital, Leeds, United Kingdom
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Potts LE, Longwell JJ, Bedocs P, Sambuughin N, Bina S, Cooper PB, Carroll CG, O'Connor F, Deuster P, Muldoon SM, Hamilton S, Capacchione JF. Improving awareness of nonanesthesia-related malignant hyperthermia presentations: a tale of two brothers. ACTA ACUST UNITED AC 2015; 3:23-6. [PMID: 25611019 DOI: 10.1213/xaa.0000000000000043] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
A 30-year-old man developed unexplained rhabdomyolysis, persistently increased creatine kinase and severe debilitating muscle cramps. After a nondiagnostic neurologic evaluation, he was referred for a muscle biopsy, to include histology/histochemistry, a myoglobinuria panel, and a caffeine halothane contracture test. Only the caffeine halothane contracture test was positive, and a subsequent ryanodine receptor type 1 gene evaluation revealed a mutation functionally causative for malignant hyperthermia. His identical twin brother, who was suffering from similar complaints, was found to share the same mutation. They each require oral dantrolene therapy to control symptoms, despite difficulty in identifying health care providers familiar with treating this disorder.
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Affiliation(s)
- Lauren E Potts
- From the *Department of Anesthesiology, Walter Reed National Military Medical Center, Bethesda; †DVCIPM, Rockville; ‡Department of Anesthesiology, Uniformed Services University of the Health Sciences; Departments of §Neurosurgery and ‖Neurology, Walter Reed National Military Medical Center, Bethesda, Maryland; ¶Department of Military Medicine, Uniformed Services University of the Health Sciences; and **Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas
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29
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Li Y, Wang Y, Ma L. An association study of CASQ1 gene polymorphisms and heat stroke. GENOMICS, PROTEOMICS & BIOINFORMATICS 2014; 12:127-32. [PMID: 24887214 PMCID: PMC4411341 DOI: 10.1016/j.gpb.2014.03.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Accepted: 03/31/2014] [Indexed: 11/17/2022]
Abstract
Although molecular mechanisms of heat stroke under physiological and pathological conditions have not yet been elucidated, a novel disease-associated gene encoding a calcium-binding protein, calsequestrin-1 (CASQ1), was suggested relevant based on results from a transgenic murine model. Here, we show the association between single nucleotide polymorphisms (SNPs) of CASQ1 and physiological parameters for heat stroke from a study involving 150 patients. Pooled DNA from heat stroke patients were subjected to sequencing and 3 SNPs were identified. Genotypes were assigned for all patients according to g. 175A>G, one SNP which leads to a nonsynonymous substitution (N59D) in the first exon of human CASQ1 gene. We analyzed the genotypic data with a linear model based on significance scores between SNP (175A>G) and heat stroke parameters. As a result, we found a significant association between SNP A175G and heat stroke (P<0.05). Further bioinformatics analysis of the 1-Mb flanking sequence revealed the presence of two genes that encode DDB1 and CUL4 associated factor 8 (DCAF8), and peroxisomal biogenesis factor 19 (PEX19), respectively, which might be functionally related to CASQ1. Our results showed that the blood calcium of patients with allele D increased significantly, compared to patients with allele N (P<0.05), which may result from the decreased calcium in muscle, suggesting that N59D in CASQ1 might account for the dysfunction of CASQ1 in calcium regulation during heat stroke.
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Affiliation(s)
- Ying Li
- Department of Radiology, Chinese PLA Medical School, Beijing 100853, China
| | - Yu Wang
- Department of Health Medicine, Beijing Electric Power Hospital, Beijing 100073, China
| | - Lin Ma
- Department of Radiology, Chinese PLA Medical School, Beijing 100853, China.
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Thomas J, Crowhurst T. Exertional heat stroke, rhabdomyolysis and susceptibility to malignant hyperthermia. Intern Med J 2014; 43:1035-8. [PMID: 24004393 DOI: 10.1111/imj.12232] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 01/30/2013] [Indexed: 11/28/2022]
Abstract
Unexpectedly severe exertional heat stroke and rhabdomyolysis should prompt a clinician to look for susceptibility to malignant hyperthermia. We report a case of exertional heat stroke and rhabdomyolysis in a man later determined to have the malignant hyperthermia phenotype. We review the existing literature regarding this association and suggest future research that could address areas of remaining clinical uncertainty.
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Affiliation(s)
- J Thomas
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
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Stathopulos PB, Seo MD, Enomoto M, Amador FJ, Ishiyama N, Ikura M. Themes and variations in ER/SR calcium release channels: structure and function. Physiology (Bethesda) 2013; 27:331-42. [PMID: 23223627 DOI: 10.1152/physiol.00013.2012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Calcium (Ca(2+)) release from reticular stores is a vital regulatory signal in eukaryotes. Recent structural data on large NH(2)-terminal regions of IP(3)Rs and RyRs and their tetrameric arrangement in the full-length context reveal striking mechanistic similarities in Ca(2+) release channel function. A common ancestor found in unicellular genomes underscores the fundamentality of these elements to Ca(2+) release channels.
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Affiliation(s)
- Peter B Stathopulos
- Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
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Yarotskyy V, Protasi F, Dirksen RT. Accelerated activation of SOCE current in myotubes from two mouse models of anesthetic- and heat-induced sudden death. PLoS One 2013; 8:e77633. [PMID: 24143248 PMCID: PMC3797063 DOI: 10.1371/journal.pone.0077633] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Accepted: 09/11/2013] [Indexed: 11/24/2022] Open
Abstract
Store-operated calcium entry (SOCE) channels play an important role in Ca2+ signaling. Recently, excessive SOCE was proposed to play a central role in the pathogenesis of malignant hyperthermia (MH), a pharmacogenic disorder of skeletal muscle. We tested this hypothesis by characterizing SOCE current (ISkCRAC) magnitude, voltage dependence, and rate of activation in myotubes derived from two mouse models of anesthetic- and heat-induced sudden death: 1) type 1 ryanodine receptor (RyR1) knock-in mice (Y524S/+) and 2) calsequestrin 1 and 2 double knock-out (dCasq-null) mice. ISkCRAC voltage dependence and magnitude at -80 mV were not significantly different in myotubes derived from wild type (WT), Y524S/+ and dCasq-null mice. However, the rate of ISkCRAC activation upon repetitive depolarization was significantly faster at room temperature in myotubes from Y524S/+ and dCasq-null mice. In addition, the maximum rate of ISkCRAC activation in dCasq-null myotubes was also faster than WT at more physiological temperatures (35-37°C). Azumolene (50 µM), a more water-soluble analog of dantrolene that is used to reverse MH crises, failed to alter ISkCRAC density or rate of activation. Together, these results indicate that while an increased rate of ISkCRAC 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.
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Affiliation(s)
- Viktor Yarotskyy
- Department of Physiology and Pharmacology, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Feliciano Protasi
- Center for Research on Ageing & Department of Neuroscience and Imaging, Università Gabriele d'Annunzio, Chieti, Italy
| | - Robert T. Dirksen
- Department of Physiology and Pharmacology, University of Rochester Medical Center, Rochester, New York, United States of America
- * E-mail:
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Abstract
Heat stroke represents the extreme end of a spectrum of heat-related illnesses. It can occur in endurance athletes. Its incidence is probably under-reported. Patients present confused, drowsy or comatose, with a raised core temperature, but often a falsely reassuring peripheral temperature. Treatment is centred on reducing the core temperature as rapidly as possible and appropriate supportive management. Even with prompt treatment, it is associated with multi-organ dysfunction and death. Patients are often misdiagnosed, or diagnosed late. This is probably exacerbated by a wide differential diagnosis, the need for a core temperature measurement to reach the diagnosis and clinicians being unfamiliar with the disease. The need for immediate recognition, and immediate treatment compounds the problem. Survivors may experience long-term neurological disability and may be at risk of a further episode. Patients should return to sport gradually and only when they feel well. Its epidemiology, pathophysiology and clinical management are reviewed.
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Affiliation(s)
- Edward Walter
- Intensive Care Specialist Registrar, Royal Sussex County Hospital, Brighton
| | - Richard Venn
- Intensive Care Consultant, Western Sussex Hospitals NHS Trust, Worthing
| | - Tim Stevenson
- Occupational Health and Sports Physician, Managing Director, Healthy Company, Medical Director, Brighton Marathon
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Abstract
The increasing popularity of mass participation endurance events necessitates that on-site medical teams be well versed in the management of both common and life-threatening conditions. Exertional heat stroke is one such condition, which if left untreated can be fatal.
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AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation. Nat Med 2012; 18:244-51. [PMID: 22231556 PMCID: PMC3274651 DOI: 10.1038/nm.2598] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2011] [Accepted: 11/08/2011] [Indexed: 11/08/2022]
Abstract
Mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (RyR1) die when exposed to short periods of temperature elevation (≥ 37 °C). We demonstrate that treatment with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) prevents heat-induced sudden death in Y524S mice. The AICAR protection is independent of AMPK activation and results from a newly identified action on the mutant RyR1 to reduce Ca2+ leak, preventing Ca2+ dependent increases in both reactive oxygen and reactive nitrogen species that act to further increase resting Ca2+ concentrations. If unchecked, the temperature driven increases in resting Ca2+ and ROS/RNS create an amplifying cycle that ultimately triggers sustained muscle contractions, rhabdomyolysis and death. Although antioxidants are effective in reducing this cycle in vitro, only AICAR prevents the heat induced death in vivo. Our findings suggest that AICAR is likely to be effective in prophylactic treatment of humans with enhanced susceptibility to exercise/heat-induced sudden death associated with RyR1 mutations.
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Ryanodine Receptor Physiology and Its Role in Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 740:217-34. [DOI: 10.1007/978-94-007-2888-2_9] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Protasi F, Paolini C, Canato M, Reggiani C, Quarta M. Lessons from calsequestrin-1 ablation in vivo: much more than a Ca(2+) buffer after all. J Muscle Res Cell Motil 2011; 32:257-70. [PMID: 22130610 DOI: 10.1007/s10974-011-9277-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Accepted: 11/09/2011] [Indexed: 10/15/2022]
Abstract
Calsequestrin type-1 (CASQ1), the main sarcoplasmic reticulum (SR) Ca(2+) binding protein, plays a dual role in skeletal fibers: a) it provides a large pool of rapidly-releasable Ca(2+) during excitation-contraction (EC) coupling; and b) it modulates the activity of ryanodine receptors (RYRs), the SR Ca(2+) release channels. We have generated a mouse lacking CASQ1 in order to further characterize the role of CASQ1 in skeletal muscle. Contrary to initial expectations, CASQ1 ablation is compatible with normal motor activity, in spite of moderate muscle atrophy. However, CASQ1 deficiency results in profound remodeling of the EC coupling apparatus: shrinkage of junctional SR lumen; proliferation of SR/transverse-tubule contacts; and increased density of RYRs. While force development during a twitch is preserved, it is nevertheless characterized by a prolonged time course, likely reflecting impaired Ca(2+) re-uptake by the SR. Finally, lack of CASQ1 also results in increased rate of SR Ca(2+) depletion and inability of muscle to sustain tension during a prolonged tetani. All modifications are more pronounced (or only found) in fast-twitch extensor digitorum longus muscle compared to slow-twitch soleus muscle, likely because the latter expresses higher amounts of calsequestrin type-2 (CASQ2). Surprisingly, male CASQ1-null mice also exhibit a marked increased rate of spontaneous mortality suggestive of a stress-induced phenotype. Consistent with this idea, CASQ1-null mice exhibit an increased susceptibility to undergo a hypermetabolic syndrome characterized by whole body contractures, rhabdomyolysis, hyperthermia and sudden death in response to halothane- and heat-exposure, a phenotype remarkably similar to human malignant hyperthermia and environmental heat-stroke. The latter findings validate the CASQ1 gene as a candidate for linkage analysis in human muscle disorders.
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Affiliation(s)
- Feliciano Protasi
- CeSI-Center for Research on Ageing & DNI-Department of Neuroscience and Imaging, University Gabriele d’Annunzioof Chieti, Via Colle dell’Ara, 66100 Chieti, Italy.
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Noakes TD. Is it time to retire the A.V. Hill Model?: A rebuttal to the article by Professor Roy Shephard. Sports Med 2011; 41:263-77. [PMID: 21425886 DOI: 10.2165/11583950-000000000-00000] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Recent publications by Emeritus Professor Roy Shephard propose that a "small group of investigators who have argued repeatedly (over the past 13 years) for a 'Central Governor'," should now either "Put up or shut up." Failing this, their 'hypothesis' should be 'consigned to the bottom draw for future reference'; but Professor Shephard's arguments are contradictory. Thus, in different sections of his article, Professor Shephard explains: why there is no need for a brain to regulate exercise performance; why there is no proof that the brain regulates exercise performance; and why the brain's proven role in the regulation of exercise performance is already so well established that additional comment and research is unnecessary. Hence, "The higher centres of an endurance athlete … call forth an initial effort … at a level where a minimal accumulation of lactate in the peripheral muscles is sensed." Furthermore, "a variety of standard texts have illustrated the many mutually redundant feedback loops (to the nervous system) that limit exercise." Yet, the figure from Professor Shephard's 1982 textbook does not contain any links between the nervous system, "many mutually redundant feedback loops" and skeletal muscle. This disproves his contradictory claims that although there is neither any need for, nor any proof of, any role of the brain in the regulation of exercise performance, the physiological mechanisms for this (non-existent) control were already well established in 1982. In contrast, the Central Governor Model (CGM) developed by our "small group … in a single laboratory" after 1998, provides a simple and unique explanation of how 'redundant feedback loops' can assist in the regulation of exercise behaviour. In this rebuttal to his article, I identify (i) the numerous contradictions included in Professor Shephard's argument; (ii) the real meaning of the facts that he presents; (iii) the importance of the evidence that he ignores; and (iv) the different philosophies of how science should be conducted according to either the Kuhnian or the Popperian philosophies of scientific discovery. My conclusion is that the dominance of an authoritarian Kuhnian philosophy, which refuses to admit genuine error or "the need to alter one's course of belief or action," explains why there is little appetite in the exercise sciences for the acceptance of genuinely novel ideas such as the CGM. Furthermore, to advance the case for the CGM, I now include evidence from more than 30 studies, which, in my opinion, can only be interpreted according to a model of exercise regulation where the CNS, acting in an anticipatory manner, regulates the exercise behaviour by altering skeletal muscle recruitment, specifically to ensure that homeostasis is maintained during exercise. Since few, if any, of those studies can be explained by the 'brainless' A.V. Hill Cardiovascular Model on which Professor Shephard bases his arguments, I argue that it is now the appropriate time to retire that model. Perhaps this will bring to an end the charade that holds either (i) that the brain plays no part in the regulation of exercise performance; or, conversely, (ii) that the role of the brain is already so well defined that further research by other scientists is unnecessary. However, this cannot occur in a discipline that is dominated by an authoritarian Kuhnian philosophy.
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Affiliation(s)
- Timothy D Noakes
- Discovery Health Chair of Exercise and Sports Science, UCT/MRC Research Unit for Exercise Science and Sports Medicine, University of Cape Town, Cape Town, South Africa.
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Capacchione JF, Muldoon SM. The relationship between exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia. Anesth Analg 2009; 109:1065-9. [PMID: 19617585 DOI: 10.1213/ane.0b013e3181a9d8d9] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia (MH) are complex syndromes with similar pathophysiology. All three are hypermetabolic states that include high demand for adenosine triphosphate, accelerated oxidative, chemical, and mechanical stress of muscle, and uncontrolled increase in intracellular calcium. Although there are no controlled clinical studies to support a relationship, there is evidence to suggest an association between unexpected heat/exercise intolerance and MH susceptibility. There are multiple case reports and a small number of clinical studies that have used in vitro muscle contracture testing and/or genetic testing to make the association. However, such methodology is problematic in that these tests are validated for clinical MH in association with anesthesia, and not for exertional heat illness or exertional rhabdomyolysis. Nevertheless, these relationships may have implications for some MH-susceptible patients and their capacity to exercise, as well as for clinicians treating and anesthetizing patients with histories of unexplained exertional heat and exercise illnesses.
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Affiliation(s)
- John F Capacchione
- Department of Anesthesiology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA.
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40
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Protasi F, Paolini C, Dainese M. Calsequestrin-1: a new candidate gene for malignant hyperthermia and exertional/environmental heat stroke. J Physiol 2009; 587:3095-100. [PMID: 19417098 PMCID: PMC2727019 DOI: 10.1113/jphysiol.2009.171967] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2009] [Accepted: 05/05/2009] [Indexed: 12/24/2022] Open
Abstract
Malignant hyperthermia (MH) and exertional/environmental heat stroke (EHS) in humans present as similar life threatening crises triggered by volatile anaesthetics and strenuous exercise and/or high temperature, respectively. Many families (70-80%) diagnosed with MH susceptibility (MHS), and a few with EHS, are linked to mutations in the gene for the ryanodine receptor type-1 (RyR1), Ca(2+) release channel of the sarcoplasmic reticulum (SR) of skeletal muscle and a key protein in excitation-contraction (EC) coupling. However, mutations in the RyR1 gene are not found in all MH families, suggesting that alternative genes remain to be identified. In our laboratory we have recently characterized a novel knockout model lacking skeletal muscle calsequestrin (CASQ1), a SR Ca(2+)-binding protein that modulates RyR1 function, and investigated whether these mice present a MH/EHS-like phenotype. Ablation of CASQ1 results in remodelling of the EC coupling apparatus and functional changes, which in male mice causes a striking increase in the rate of spontaneous mortality and susceptibility to trigger MH-like lethal episodes in response to halothane and heat stress. The demonstration that ablation of CASQ1 results in MH- and EHS-like lethal episodes validates CASQ1 as a viable candidate gene for linkage analysis in MH and EHS families where mutations in RyR1 are excluded.
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Affiliation(s)
- Feliciano Protasi
- Centro Scienze dell'Invecchiamento, Department of Basic and Applied Medical Sciences, Interuniversity Institute of Myology, University G. d'Annunzio, Chieti, Italy.
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41
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Dainese M, Quarta M, Lyfenko AD, Paolini C, Canato M, Reggiani C, Dirksen RT, Protasi F. Anesthetic- and heat-induced sudden death in calsequestrin-1-knockout mice. FASEB J 2009; 23:1710-20. [PMID: 19237502 DOI: 10.1096/fj.08-121335] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Calsequestrin-1 (CASQ1) is a moderate-affinity, high-capacity Ca(2+)-binding protein in the sarcoplasmic reticulum (SR) terminal cisternae of skeletal muscle. CASQ1 functions as both a Ca(2+)-binding protein and a luminal regulator of ryanodine receptor (RYR1)-mediated Ca(2+) release. Mice lacking skeletal CASQ1 are viable but exhibit reduced levels of releasable Ca(2+) and altered contractile properties. Here we report that CASQ1-null mice exhibit increased spontaneous mortality and susceptibility to heat- and anesthetic-induced sudden death. Exposure of CASQ1-null mice to either 2% halothane or heat stress triggers lethal episodes characterized by whole-body contractures, elevated core temperature, and severe rhabdomyolysis, which are prevented by prior dantrolene administration. The characteristics of these events are remarkably similar to analogous episodes observed in humans with malignant hyperthermia (MH) and animal models of MH and environmental heat stroke (EHS). In vitro studies indicate that CASQ1-null muscle exhibits increased contractile sensitivity to temperature and caffeine, temperature-dependent increases in resting Ca(2+), and an increase in the magnitude of depolarization-induced Ca(2+) release. These results demonstrate that CASQ1 deficiency alters proper control of RYR1 function and suggest CASQ1 as a potential candidate gene for linkage analysis in families with MH/EHS where mutations in the RYR1 gene are excluded.
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Affiliation(s)
- Marco Dainese
- Ce.S.I.-Department of Basic and Applied Medical Sciences, Interuniversity Institute of Myology, University G. d'Annunzio, I-66013 Chieti, Italy
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42
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RAE DALEE, KNOBEL GIDEONJ, MANN THERESA, SWART JEROEN, TUCKER ROSS, NOAKES TIMOTHYD. Heatstroke during Endurance Exercise. Med Sci Sports Exerc 2008; 40:1193-204. [DOI: 10.1249/mss.0b013e31816a7155] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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45
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Hopkins PM. Is there a link between malignant hyperthermia and exertional heat illness? Br J Sports Med 2007; 41:283-4; discussion 284. [PMID: 17261558 PMCID: PMC2659049 DOI: 10.1136/bjsm.2006.032516] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- P M Hopkins
- Malignant Hyperthermia Investigation Unit, Academic Unit of Anaesthesia, St James's University Hospital, Leeds, UK.
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46
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Biais M, Nouette-Gaulain K, Lelias A, Vallet A, Neau-Cransac M, Revel P, Sztark F. Coup de chaleur d'exercice avec hépatite fulminante : intérêt du système MARS® ? ACTA ACUST UNITED AC 2005; 24:1393-6. [PMID: 16099123 DOI: 10.1016/j.annfar.2005.06.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2005] [Accepted: 06/16/2005] [Indexed: 11/23/2022]
Abstract
Exertional heat stroke (EHS) is a life-threatening condition caused by an extreme elevation in core body temperature. Acute liver failure has been reported during EHS justifying liver transplantation in some cases. The Molecular Adsorbent Recirculating System (MARS) could be indicated in such situations. We report a case of a 58-year old patient who suffered acute liver failure occurring after EHS. The patient was referred for liver transplantation and benefited of MARS therapy. After three sessions of MARS, liver function improved progressively and the transplantation was not necessary. The patient completely recovered.
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Affiliation(s)
- M Biais
- Département d'anesthésie-réanimation I, CHU Pellegrin, 146, rue Leo-Saignat, 33076 Bordeaux cedex, France
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Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F. Dantrolene--a review of its pharmacology, therapeutic use and new developments. Anaesthesia 2004; 59:364-73. [PMID: 15023108 DOI: 10.1111/j.1365-2044.2004.03658.x] [Citation(s) in RCA: 367] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Human malignant hyperthermia is a life-threatening genetic sensitivity of skeletal muscles to volatile anaesthetics and depolarizing neuromuscular blocking drugs occurring during or after anaesthesia. The skeletal muscle relaxant dantrolene is the only currently available drug for specific and effective therapy of this syndrome in man. After its introduction, the mortality of malignant hyperthermia decreased from 80% in the 1960s to < 10% today. It was soon discovered that dantrolene depresses the intrinsic mechanisms of excitation-contraction coupling in skeletal muscle. However, its precise mechanism of action and its molecular targets are still incompletely known. Recent studies have identified the ryanodine receptor as a dantrolene-binding site. A direct or indirect inhibition of the ryanodine receptor, the major calcium release channel of the skeletal muscle sarcoplasmic reticulum, is thought to be fundamental in the molecular action of dantrolene in decreasing intracellular calcium concentration. Dantrolene is not only used for the treatment of malignant hyperthermia, but also in the management of neuroleptic malignant syndrome, spasticity and Ecstasy intoxication. The main disadvantage of dantrolene is its poor water solubility, and hence difficulties are experienced in rapidly preparing intravenous solutions in emergency situations. Due to economic considerations, no other similar drugs have been introduced into routine clinical practice.
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Affiliation(s)
- T Krause
- Department of Anaesthesiology, University-Hospital Hamburg-Eppendorf, Hamburg, Germany.
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49
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Abstract
OBJECTIVE: To report a case of fatal rhabdomyolysis secondary to exertional heat stroke and the potential influence of sickle cell trait on the outcome of this case. DESIGN: Descriptive case report. SETTING: Pediatric intensive care unit in an academic children's hospital. MAIN RESULTS: A description of the presentation and clinical course of exertional heatstroke with rhabdomyolysis in an adolescent athlete. The implications of the patient's clinical course and a possible connection to sickle cell trait are also discussed. CONCLUSION: Young athletes with sickle cell trait may be at an increased risk of heat-related illnesses and their complications. Epidemiologic studies are warranted to address this possibility.
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50
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Affiliation(s)
- H Grogan
- Department of Anaesthesia, Leeds Teaching Hospital Trust, UK
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