Firefighting and malignant hyperthermia

Denborough, M. A.; Hopkinson, K.C.; Banney, D G

doi:10.1136/bmj.296.6634.1442-a

Cited by 16 publications

(6 citation statements)

References 2 publications

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“…RYR1 is a large protein of about 2200 kDa specifically localized in calcium release units (CRUs), the intracellular junctions formed by the close apposition of transverse-tubules (TT) to the SR. RYR1 in CRUs is part of macromolecular complex deputed to excitation-contraction (EC) coupling, the mechanism that allows transduction of the action potential into Ca 2+ release from the SR [ 6 , 7 ]. Mutations in RYR1 gene, which causes abnormalities in the opening probability of the Ca 2+ channel, are also often associated to malignant hyperthermia (MH) susceptibility, an inherited pharmacogenetic subclinical myopathy, characterized by a life-threatening hypermetabolic response to commonly used halogenated/volatile anesthetics (i.e., halothane, isofluorane) [ 8 , 9 ]. An association between CCD and MH exists as individuals with MH may have muscle biopsies with cores [ 10 , 11 ], while CCD patients may be at risk for hyperthermic episodes during anesthetic procedures, as also confirmed by in vitro caffeine-halothane contracture testing (either IVCT, in vitro contracture test, or the CHCT, caffeine-halothane contracture test), performed on muscle biopsies [ 2 , 12 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

Antioxidant Treatment Reduces Formation of Structural Cores and Improves Muscle Function in RYR1^Y522S/WT Mice

Michelucci

Marco

Guarnier

et al. 2017

Oxidative Medicine and Cellular Longevity

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Central core disease (CCD) is a congenital myopathy linked to mutations in the ryanodine receptor type 1 (RYR1), the sarcoplasmic reticulum Ca2+ release channel of skeletal muscle. CCD is characterized by formation of amorphous cores within muscle fibers, lacking mitochondrial activity. In skeletal muscle of RYR1Y522S/WT knock-in mice, carrying a human mutation in RYR1 linked to malignant hyperthermia (MH) with cores, oxidative stress is elevated and fibers present severe mitochondrial damage and cores. We treated RYR1Y522S/WT mice with N-acetylcysteine (NAC), an antioxidant provided ad libitum in drinking water for either 2 or 6 months. Our results show that 2 months of NAC treatment starting at 2 months of age, when mitochondrial and fiber damage was still minimal, (i) reduce formation of unstructured and contracture cores, (ii) improve muscle function, and (iii) decrease mitochondrial damage. The beneficial effect of NAC treatment is also evident following 6 months of treatment starting at 4 months of age, when structural damage was at an advanced stage. NAC exerts its protective effect likely by lowering oxidative stress, as supported by the reduction of 3-NT and SOD2 levels. This work suggests that NAC administration is beneficial to prevent mitochondrial damage and formation of cores and improve muscle function in RYR1Y522S/WT mice.

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Section: Introductionmentioning

confidence: 99%

Antioxidant Treatment Reduces Formation of Structural Cores and Improves Muscle Function in RYR1^Y522S/WT Mice

Michelucci

Marco

Guarnier

et al. 2017

Oxidative Medicine and Cellular Longevity

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“…Malignant hyperthermia (MH) susceptibility (MHS), which was identified and described for the first time in 1960 (1), is an inherited pharmacogenetic disorder characterized by a life-threatening hypermetabolic response to halogenated/volatile anesthetics (i.e., halothane or isofluorane) or to the depolarizing muscle relaxant succinylcholine (2,3). The main clinical features of MH crises include skeletal muscle rigidity, increased oxygen consumption, hyperthermia, rhabdomyolysis (i.e., the rupture of muscle fibers), myoglobinuria, and increased plasma/serum levels of K + and creatine kinase (CK), which could eventually lead to cardiac arrhythmia (and even arrest) or kidney failure.…”

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confidence: 99%

Strenuous exercise triggers a life‐threatening response in mice susceptible to malignant hyperthermia

et al. 2017

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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 (RYR1 Y522S/WT ) and calsequestrin-1 knockout (CASQ1-null), 2 proteins that control Ca 2+ release in skeletal muscle. As overheating episodes in humans have also been described during exertion, here we subjected RYR1 Y522S/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 RYR1 Y522S/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 Ca 2+ -dependent activation of calpains and NF-kB by lowering myoplasmic Ca 2+ concentration and nitro-oxidative stress, parameters that were elevated in RYR1 Y522S/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. FASEB J. 31, 3649-3662 (2017). www.fasebj.org

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“…In the past decade several additional agents have been suspected to induce MH‐like symptoms. Occupational exposure to halogenated hydrocarbons ( 8) as well as accidental inhalation of gasoline vapors ( 9) have been described as having induced acute rhabdomyolysis in MHS patients. Also, cresol derivatives, widely used as preservatives, were suspected to play a role in the development of MH‐like symptoms ( 10, 11).…”

Section: Discussionmentioning

confidence: 99%

The impact of 4‐chloro‐m‐cresol in heparin formulas on malignant hyperthermia: in vitro and in vivo

Anetseder

Ritter

Horbaschek

et al. 2000

Acta Anaesthesiol Scand

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Heparin formulas, containing 4CmC, induce dose-dependent contractures in vitro in MHS human skeletal muscle at about 60 microM 4CmC. However, in vivo, 4CmC serum concentrations with therapeutic heparinization are less than 1/15 of the in vitro concentration. The lipophilicity of 4CmC with a high volume of distribution may account for these findings. MHS patients seem not to be at risk from clinical heparin formulas containing chlorocresol.

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Firefighting and malignant hyperthermia

Cited by 16 publications

References 2 publications

Antioxidant Treatment Reduces Formation of Structural Cores and Improves Muscle Function in RYR1^Y522S/WT Mice

Antioxidant Treatment Reduces Formation of Structural Cores and Improves Muscle Function in RYR1^Y522S/WT Mice

Strenuous exercise triggers a life‐threatening response in mice susceptible to malignant hyperthermia

The impact of 4‐chloro‐m‐cresol in heparin formulas on malignant hyperthermia: in vitro and in vivo

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Firefighting and malignant hyperthermia

Cited by 16 publications

References 2 publications

Antioxidant Treatment Reduces Formation of Structural Cores and Improves Muscle Function in RYR1Y522S/WT Mice

Antioxidant Treatment Reduces Formation of Structural Cores and Improves Muscle Function in RYR1Y522S/WT Mice

Strenuous exercise triggers a life‐threatening response in mice susceptible to malignant hyperthermia

The impact of 4‐chloro‐m‐cresol in heparin formulas on malignant hyperthermia: in vitro and in vivo

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Antioxidant Treatment Reduces Formation of Structural Cores and Improves Muscle Function in RYR1^Y522S/WT Mice

Antioxidant Treatment Reduces Formation of Structural Cores and Improves Muscle Function in RYR1^Y522S/WT Mice