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TOXICOLOGY

The Role of Mitochondrial Uncoupling in 3,4-Methylenedioxymethamphetamine-Mediated Skeletal Muscle Hyperthermia and Rhabdomyolysis

Departments of Emergency Medicine (D.E.R., S.L.T.), Pharmacology and Toxicology (D.E.R., D.J.S.), and Radiology (N.B., S.K.H.), Indiana University School of Medicine, Indianapolis, Indiana; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (E.M.); Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada (D.M., M.-E.H.); and Virginia College of Osteopathic Medicine, Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, Virginia (J.E.S.)

Use of the popular club drug ecstasy (3,4-methylenedioxymethamphetamine, MDMA) can result in life-threatening hyperthermia and rhabdomyolysis. Recent studies show a link between skeletal muscle uncoupling proteins in MDMA-mediated hyperthermia. The mechanisms by which MDMA interacts with skeletal muscle mitochondria are largely unknown. The present study was designed to comprehensively evaluate the effects of MDMA on bioenergetics and toxicity of skeletal muscle. Using ³¹P nuclear magnetic resonance (NMR) and serum creatine kinase levels, we demonstrate evidence for uncoupling of oxidative phosphorylation in the skeletal muscle of MDMA (40 mg/kg)-treated rats. In vivo, rats treated with MDMA had significantly elevated serum creatine kinase levels, a marker of rhabdomyolysis, 4 h post-MDMA treatment (955 ± 132 IU/l) compared with saline-treated controls (373.2 ± 59 IU/l). -ATP signal areas after MDMA treatment showed significant reductions (15%) from the baseline values with corresponding increases in inorganic phosphate (88% increases) and decreases in intracellular pH. Clark electrode experiments on isolated skeletal muscle mitochondria in vitro (1–5 mM MDMA) and ex vivo in MDMA-treated animals demonstrated no evidence of uncoupling of oxidative phosphorylation. In vitro experiments using L6 myotubules cocultured with primary hepatocytes demonstrated the presence of uncoupling protein-3 in the L6 myotubules, but no evidence of a direct effect of MDMA or its potential metabolites on cellular creatine kinase concentrations. These findings suggest that MDMA uncouples skeletal muscle mitochondria in vivo but that this uncoupling is the result of indirect mechanisms.

Address correspondence to: Dr. Daniel E Rusyniak, Regenstrief Health Center, Suite R2200, 1050 Wishard Boulevard, Indianapolis, IN 46202-2859. E-mail: drusynia{at}iupui.edu

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