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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 11, 2005; DOI: 10.1124/jpet.104.079236

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Received for publication October 13, 2004.
Revised January 10, 2005.
Accepted for publication January 10, 2005.

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

Daniel E. Rusyniak 1*, Stephany L. Tandy 1, Shahrya N. Hekmatyar 1, Edward Mills 2, David J. Smith 3, Navin Bansal 3, Darcy MacLellan 4, Mary-Ellen Harper 4, Jon E. Sprague 5

1 Indiana University School of Medicine 2 NHLBI / NIH 3 Indiana Univeristy School of Medicine 4 University of Ottawa 5 Virginia College of Osteopathic Medicine, Virginia Polytechnic Institute and State University

* Address correspondence to: E-mail: drusynia{at}iupui.edu

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 (CK) 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 CK levels, a marker of rhabdomyolysis, fours hours post MDMA treatment (955 +/- 132 IU/L) compared to saline treated controls (373.2 +/- 59 IU/L). {beta}-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 co-cultured with primary hepatocytes demonstrated the presence of UCP-3 in the L6 myotubules, but no evidence of a direct effect of MDMA or its potential metabolites on cellular CK concentrations. These findings suggest that MDMA uncouples skeletal muscle mitochondria in vivo but that this uncoupling is the result of indirect mechanisms.


Key words: 3,4-methylenedioxymethamphetamine, Nuclear Magnetic Resonance, Oxidative Phosphorylation, Skeletal Muscle, Uncoupling Agents, rhabdomyolysis


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