Fatty Acids: Potentially Crucial Modulators of the Malignant Hyperthermia Syndrome

  • Jeffrey E. Fletcher
  • Steven J. Wieland
Conference paper


While defects in the ryanodine receptor may in some cases be necessary to impart the potential for malignant hyperthermia (MH) susceptibility, these defects are not sufficient to account for the MH syndrome. Obvious examples include swine homozygous for the proposed ryanodine receptor arginine to cysteine #615 MH mutation that do not exhibit an MH reaction at a young age [1] and those that do not consistently exhibit a reaction even as an adult, despite the administration of more than adequate amounts of triggering agents [2].


Free Fatty Acid Sodium Channel Sarcoplasmic Reticulum Ryanodine Receptor Human Skeletal Muscle 


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  1. 1.
    Cheah KS, Cheah AM, Waring JC (1986) Phospholipase A2 activity, calmodulin, Ca2+ and meat quality in young and adult halothane-sensitive and halothane-insensitive British Landrace pigs. Meat Sci 17: 37–53PubMedCrossRefGoogle Scholar
  2. 2.
    Fletcher JE, Calvo PA, Rosenberg H (1993) Phenotypes associated with malignant hyperthermia susceptibility in swine genotyped as homozygous or heterozygous for the ryanodine receptor mutation. Br J Anaesth 71: 410–417PubMedCrossRefGoogle Scholar
  3. 3.
    Hawkes MJ, Nelson TE, Hamilton SL (1992) [3H]Ryanodine as a probe of changes in the functional state of the Ca2+-release channel in malignant hyperthermia. J Biol Chem 267: 6702–6709PubMedGoogle Scholar
  4. 4.
    Fletcher JE, Tripolitis L, Rosenberg H, Beech J (1993) Malignant hyperthermia: halothane-and calcium-induced calcium release in skeletal muscle. Biochem Mol Biol Int 29: 763–772PubMedGoogle Scholar
  5. 5.
    Catterall WA (1992) Cellular and molecular biology of voltage-gated sodium channels. Physiol Rev 72: S15 - S48PubMedGoogle Scholar
  6. 6.
    Vital Brazil O, Fontana MD (1983) Review article—Toxins as tools in the study of sodium channel distribution in the muscle fibre membrane. Toxicon 31: 1085–1098CrossRefGoogle Scholar
  7. 7.
    Nelson TE (1983) Abnormality in calcium release from skeletal sarcoplasmic reticulum of pigs susceptible to malignant hyperthermia. J Clin Invest 72: 862–870PubMedCrossRefGoogle Scholar
  8. 8.
    Ohnishi ST, Taylor S, Gronert GA (1983) Calcium-induced Ca2+ release from sarcoplasmic reticulum of pigs susceptible to malignant hyperthermia: the effects of halothane and dantrolene. FEBS Lett 161: 103–107PubMedCrossRefGoogle Scholar
  9. 9.
    Kim DH, Sreter FA, Ohnishi ST, Ryan JF, Roberts J, Allen PD, Meszaros LG, Antoniu B, Ikemoto N (1984) Kinetic studies of Ca2+ release from sarcoplasmic reticulum of normal and malignant hyperthermia-susceptible pig muscles. Biochim Biophys Acta 775: 320–327PubMedCrossRefGoogle Scholar
  10. 10.
    Mickelson JR, Ross JA, Reed BK, Louis CF (1986) Enhanced Ca2+-induced calcium release by isolated sarcoplasmic reticulum vesicles from malignant hyperthermiasusceptible pig muscle. Biochim Biophys Acta 862: 318–328PubMedCrossRefGoogle Scholar
  11. 11.
    Fletcher JE, Mayerberger S, Tripolitis L, Yudkowsky M, Rosenberg H (1991) Fatty acids markedly lower the threshold for halothane-induced calcium release from the terminal cisternae in human and porcine normal and malignant hyperthermia-susceptible skeletal muscle. Life Sci 49: 1651–1657PubMedCrossRefGoogle Scholar
  12. 12.
    Nelson TE, Lin M, Volpe P (1991) Evidence for intraluminal Ca2+ regulatory site defect in sarcoplasmic reticulum from malignant hyperthermia pig muscle. J Pharmacol Exp Ther 256: 645–649PubMedGoogle Scholar
  13. 13.
    Fill M, Stefani E, Nelson TE (1991) Abnormal human sarcoplasmic reticulum Carr release channels in malignant hyperthermic skeletal muscle. Biophys J 59: 1085–1090PubMedCrossRefGoogle Scholar
  14. 14.
    Nelson TE (1992) Halothane effects on human malignant hyperthermia skeletal muscle single calcium-release channels in planar lipid bilayers. Anesthesiology 76: 588–595PubMedCrossRefGoogle Scholar
  15. 15.
    Wieland SJ, Fletcher JE, Rosenberg H, Gong QH (1989) Malignant hyperthermia: slow sodium current in cultured human muscle cells. Am J Physiol 257: C759 - C765PubMedGoogle Scholar
  16. 16.
    Wieland SJ, Gong Q-H, Fletcher JE, Rosenberg H (1992) Fatty acid activation of silent sodium channels in cultured human skeletal muscle. Anesthesiology 77: A761CrossRefGoogle Scholar
  17. 17.
    Wieland SJ, Fletcher JE, Gong Q-H, Rosenberg H (1991) Effects of lipid-soluble agents on sodium channel function in normal and MH-susceptible skeletal muscle cultures. In: Blanck TJJ, Wheeler DM (eds) Mechanisms of anesthetic action in muscle. Plenum, New York, pp 9–19CrossRefGoogle Scholar
  18. 18.
    Ruppersberg JP, Rudel R (1988) Differential effects of halothane on adult and juvenile sodium channels in human muscle. Pflügers Arch 412: 17–21PubMedGoogle Scholar
  19. 19.
    Cheah KS, Cheah AM (1981) Skeletal muscle mitochondrial phospholipase A2 and the interaction of mitochondria and sarcoplasmic reticulum in porcine malignant hyperthermia. Biochim Biophys Acta 638: 40–49PubMedCrossRefGoogle Scholar
  20. 20.
    Fletcher JE, Rosenberg H (1986) In vitro muscle contractures induced by halothane and suxamethonium: II. Human skeletal muscle from normal and malignant hyperthermia-susceptible patients. Br J Anaesth 58: 1433–1439PubMedCrossRefGoogle Scholar
  21. 21.
    Foster PS, Gesini E, Claudianos C, Hopkinson KC, Denborough MA (1989) Inositol 1,4,5,-trisphosphate phosphatase deficiency and malignant hyperpyrexia in swine. Lancet 1: 124–126CrossRefGoogle Scholar
  22. 22.
    Scholz J, Roewer N, Rum U, Schmitz W, Scholz H, Schulte am Esch J (1991) Possible involvement of inositol-lipid metabolism in malignant hyperthermia. Br J Anaesth 66: 692–696PubMedCrossRefGoogle Scholar
  23. 23.
    Scholz J, Troll U, Schulte am Esch J, Hartung E, Patten M, Sandig P, Schmitz W (1991) Inositol-1,4,5-trisphosphate and malignant hyperthermia. Lancet 337: 1361PubMedCrossRefGoogle Scholar
  24. 24.
    Duthie GG, Arthur JR (1993) Free radicals and calcium homeostasis: relevance to malignant hyperthermia. Free Radical Biol Med 14: 435–442CrossRefGoogle Scholar
  25. 25.
    Fletcher JE, Rosenberg H, Michaux K, Tripolitis L, Lizzo FH (1989) Triglycerides, not phospholipids, are the source of elevated free fatty acids in muscle from patients susceptible to malignant hyperthermia. Eur J Anaesth 6: 355–362Google Scholar
  26. 26.
    Fletcher JE, Tripolitis L, Erwin K, Hanson S, Rosenberg H, Conti PA, Beech J (1990) Fatty acids modulate calcium-induced calcium release from skeletal muscle heavy sarcoplasmic reticulum fractions: implications for malignant hyperthermia. Biochem Cell Biol 68: 1195–1201PubMedCrossRefGoogle Scholar
  27. 27.
    Olgin J, Rosenberg H, Allen G, Seestedt R, Chance B (1991) A blinded comparison of noninvasive, in vivo phosphorus nuclear magnetic resonance spectroscopy and the in vitro halothane/caffeine contracture test in the evaluation of malignant hyperthermia susceptibility. Anesth Analg 72: 36–47PubMedCrossRefGoogle Scholar
  28. 28.
    Vladutiu GD, Hogan K, Saponara I, Tassini L, Conroy J (1993) Carnitine palmitoyl transferase deficiency in malignant hyperthermia. Muscle Nerve 16: 485–491PubMedCrossRefGoogle Scholar
  29. 29.
    Fletcher JE, Rosenberg H, Michaux K, Cheah KS, Cheah AM (1988) Lipid analysis of skeletal muscle from pigs susceptible to malignant hyperthermia. Biochem Cell Biol 66: 917–921PubMedCrossRefGoogle Scholar
  30. 30.
    Fulceri R, Nori A, Gamberucci A, Volpe P, Giunti R, Benedetti A (1994) Fatty acyl-CoA esters induce calcium release from terminal cisternae of skeletal muscle. Cell Calcium 15: 109–116PubMedCrossRefGoogle Scholar
  31. 31.
    Fujii J, Otsu K, Zorzato F, de Leon S, Khanna VK, Weiler JE, O’Brien PJ, MacLennan DH (1991) Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science 253: 448–451PubMedCrossRefGoogle Scholar
  32. 32.
    Cheah AM (1981) Effect of long chain unsaturated fatty acids on the calcium transport of sarcoplasmic reticulum. Biochim Biophys Acta 648: 113–119PubMedCrossRefGoogle Scholar
  33. 33.
    Dettbarn C, Palade P (1993) Arachidonic acid-induced Cat+ release from isolated sarcoplasmic reticulum. Biochem Pharmacol 45: 1301–1309PubMedCrossRefGoogle Scholar
  34. 34.
    Grand RJA (1989) Acylation of viral and eukaryotic proteins. Biochem J 258: 625–638PubMedGoogle Scholar
  35. 35.
    Wieland SJ, Fletcher JE, Gong Q-H (1992) Differential modulation of a sodium conductance in skeletal muscle by intracellular and extracellular fatty acids. Am J Physiol 263: C308 - C312PubMedGoogle Scholar
  36. 36.
    Fletcher JE, Erwin K, Beech J (1993) Phenytoin increases specific triacylglycerol fatty esters in skeletal muscle from horses with hyperkalemic periodic paralysis. Biochim Biophys Acta 1168: 292–298PubMedGoogle Scholar
  37. 37.
    Bennett PB Jr, Makita N, George AL Jr (1993) A molecular basis for gating mode transitions in human skeletal muscle Na+ channels. FEBS Lett 326: 21–24PubMedCrossRefGoogle Scholar
  38. 38.
    Chahine M, Bennett PB, George AL Jr, Horn R (1994) Functional expression and properties of the human skeletal muscle sodium channel. Pflügers Arch 427: 136–142PubMedCrossRefGoogle Scholar
  39. 39.
    Makita N, Bennett PB Jr, George AL Jr (1994) Voltage-gated Na + channel 13, subunit mRNA expressed in adult human skeletal muscle, heart, and brain is encoded by a single gene. J Biol Chem 269: 7571–7578PubMedGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 1996

Authors and Affiliations

  • Jeffrey E. Fletcher
    • 1
  • Steven J. Wieland
    • 2
  1. 1.Department of AnesthesiologyHahnemann UniversityPhiladelphiaUSA
  2. 2.Department of AnatomyHahnemann UniversityPhiladelphiaUSA

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