Barbara Bojko1,2, Tijana Vasiljevic1, Ezel Boyaci1,3, Anna Roszkowska1,4, Natalia Kraeva5, Carlos A Ibarra Moreno5, Annabel Koivu5, Marcin Wąsowicz5, Amy Hanna6, Susan Hamilton6, Sheila Riazi7, Janusz Pawliszyn1. 1. Department of Chemistry, University of Waterloo, Waterloo, ON, Canada. 2. Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland. 3. Department of Chemistry, Middle East Technical University, Ankara, Turkey. 4. Department of Pharmaceutical Chemistry, Medical University of Gdansk, Gdansk, Poland. 5. Malignant Hyperthermia Investigation Unit, Department of Anesthesia, University Health Network, University of Toronto, 323-200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada. 6. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA. 7. Malignant Hyperthermia Investigation Unit, Department of Anesthesia, University Health Network, University of Toronto, 323-200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada. Sheila.Riazi@uhn.ca.
Abstract
PURPOSE: Malignant hyperthermia (MH) is a potentially fatal hypermetabolic condition triggered by certain anesthetics and caused by defective calcium homeostasis in skeletal muscle cells. Recent evidence has revealed impairment of various biochemical pathways in MH-susceptible patients in the absence of anesthetics. We hypothesized that clinical differences between MH-susceptible and control individuals are reflected in measurable differences in myoplasmic metabolites. METHODS: We performed metabolomic profiling of skeletal muscle samples from MH-negative (control) individuals and MH-susceptible patients undergoing muscle biopsy for diagnosis of MH susceptibility. Cellular metabolites were extracted from 33 fresh and 87 frozen human muscle samples using solid phase microextraction and Metabolon® untargeted biochemical profiling platforms, respectively. Ultra-performance liquid chromatography-high resolution mass spectrometry was used for metabolite identification and validation, followed by analysis of differences in metabolites between the MH-susceptible and MH-negative groups. RESULTS: Significant fold-change differences between the MH-susceptible and control groups in metabolites from various pathways were found (P value range: 0.009 to < 0.001). These included accumulation of long chain acylcarnitines, diacylglycerols, phosphoenolpyruvate, histidine pathway metabolites, lysophosphatidylcholine, oxidative stress markers, and phosphoinositols, as well as decreased levels of monoacylglycerols. The results from both analytical platforms were in agreement. CONCLUSION: This metabolomics study indicates a shift from utilization of carbohydrates towards lipids for energy production in MH-susceptible individuals. This shift may result in inefficiency of beta-oxidation, and increased muscle protein turnover, oxidative stress, and/or lysophosphatidylcholine levels.
PURPOSE:Malignant hyperthermia (MH) is a potentially fatal hypermetabolic condition triggered by certain anesthetics and caused by defective calcium homeostasis in skeletal muscle cells. Recent evidence has revealed impairment of various biochemical pathways in MH-susceptible patients in the absence of anesthetics. We hypothesized that clinical differences between MH-susceptible and control individuals are reflected in measurable differences in myoplasmic metabolites. METHODS: We performed metabolomic profiling of skeletal muscle samples from MH-negative (control) individuals and MH-susceptible patients undergoing muscle biopsy for diagnosis of MH susceptibility. Cellular metabolites were extracted from 33 fresh and 87 frozen human muscle samples using solid phase microextraction and Metabolon® untargeted biochemical profiling platforms, respectively. Ultra-performance liquid chromatography-high resolution mass spectrometry was used for metabolite identification and validation, followed by analysis of differences in metabolites between the MH-susceptible and MH-negative groups. RESULTS: Significant fold-change differences between the MH-susceptible and control groups in metabolites from various pathways were found (P value range: 0.009 to < 0.001). These included accumulation of long chain acylcarnitines, diacylglycerols, phosphoenolpyruvate, histidine pathway metabolites, lysophosphatidylcholine, oxidative stress markers, and phosphoinositols, as well as decreased levels of monoacylglycerols. The results from both analytical platforms were in agreement. CONCLUSION: This metabolomics study indicates a shift from utilization of carbohydrates towards lipids for energy production in MH-susceptible individuals. This shift may result in inefficiency of beta-oxidation, and increased muscle protein turnover, oxidative stress, and/or lysophosphatidylcholine levels.
Authors: Robert A van den Berg; Huub C J Hoefsloot; Johan A Westerhuis; Age K Smilde; Mariët J van der Werf Journal: BMC Genomics Date: 2006-06-08 Impact factor: 3.969
Authors: Kyuil Cho; Bradley S Evans; B McKay Wood; Ritesh Kumar; Tobias J Erb; Benjamin P Warlick; John A Gerlt; Jonathan V Sweedler Journal: Metabolomics Date: 2014-09-03 Impact factor: 4.290