The role of mitochondrial uncoupling in 3,4-methylenedioxymethamphetamine- mediated skeletal muscle hyperthermia and rhabdomyolysis

Daniel E. Rusyniak, Stephany L. Tandy, S. K. Hekmatyar, Edward Mills, David J. Smith, Navin Bansal, Darcy MacLellan, Mary Ellen Harper, Jon E. Sprague

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

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/I) compared with saline-treated controls (373.2 ± 59 IU/I). β-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.

Original languageEnglish (US)
Pages (from-to)629-639
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume313
Issue number2
DOIs
StatePublished - May 1 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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