Strenuous exercise aggravates MDMA-induced skeletal muscle damage in mice

Duarte, José Alberto; Leão, Anabela Costa; Magalhães, José; Ascensão, António; Bastos, Maria de Lourdes; Amado, Francisco; Vilarinho, Laura; Quelhas, Dulce; Appell, H.-J.; Carvalho, Félix

doi:10.1016/j.tox.2004.07.012

Cited by 19 publications

(8 citation statements)

References 27 publications

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“…It is possible that other creatine kinase isoforms, including MB, may have also contributed to the total creatine kinase increases we saw. A recent study showing structural damage to the skeletal muscle of MDMA-treated mice, however, supports that the creatine kinases in our study are secondary to skeletal muscle release (Duarte et al, 2005).…”

Section: Discussionsupporting

confidence: 77%

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

Rusyniak¹,

Tandy²,

Hekmatyar³

et al. 2005

The Journal of Pharmacology and Experimental Therapeutics

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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 31 P 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 Ϯ 132 IU/l) compared with saline-treated controls (373.2 Ϯ 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.

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Section: Discussionsupporting

confidence: 77%

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

Rusyniak¹,

Tandy²,

Hekmatyar³

et al. 2005

The Journal of Pharmacology and Experimental Therapeutics

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“…Previous research has shown that exercise potentiates the toxicity and hyperthermia of MDMA 32,33,34 . Reports on the effect of exercise on skeletal muscle UCP expression are inconsistent.…”

Section: Discussionmentioning

confidence: 99%

Potentiation of Ecstasy-induced hyperthermia and FAT/CD36 expression in chronically exercised animals

et al. 2016

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Fatal hyperthermia as a result of 3,4-methylenedioxymethamphetamine (MDMA) use involves non-esterified free fatty acids (NEFA) and the activation of mitochondrial uncoupling proteins (UCP). NEFA gain access into skeletal muscle via specific transport proteins, including fatty acid translocase (FAT/CD36). FAT/CD36 expression is known to increase following chronic exercise. Previous studies have demonstrated the essential role of NEFA and UCP3 in MDMA-induced hyperthermia. The aims of the present study were to use a chronic exercise model (swimming for two consecutive hours per day, five days per wk for six wk) to increase FAT/CD36 expression in order to: 1) determine the contribution of FAT/CD36 in MDMA (20 mg/kg, s.c.)-mediated hyperthermia; and 2) examine the effects of the FAT/CD36 inhibitor, SSO (sulfo-N-succinimidyl oleate), on MDMA-induced hyperthermia in chronic exercise and sedentary control rats. MDMA administration resulted in hyperthermia in both sedentary and chronic exercise animals. However, MDMA-induced hyperthermia was significantly potentiated in the chronic exercise animals compared to sedentary animals. Additionally, chronic exercise significantly reduced body weight, increased FAT/CD36 protein expression levels and reduced plasma NEFA levels. The FAT/CD36 inhibitor, SSO (40 mg/kg, ip), significantly attenuated the hyperthermia mediated by MDMA in chronic exercised but not sedentary animals. Plasma NEFA levels were elevated in sedentary and exercised animals treated with SSO prior to MDMA suggesting attenuation of NEFA uptake into skeletal muscle. Chronic exercise did not alter skeletal muscle UCP3 protein expression levels. In conclusion, chronic exercise potentiates MDMA-mediated hyperthermia in a FAT/CD36 dependent fashion.

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“…Unsurprisingly, even though catastrophic hyperthermia is a relatively rare event in MDMA use, one of the most commonly reported subjective effects of MDMA in humans is a feeling of “being hot” 65 . The idea that MDMA disrupts central regulation of body temperature is supported by observations that environmental ambient temperature and physical activity can profoundly affect the variability of MDMA-hyperthermic responses 66,67 . In rodent models, hyperthermia occurs when MDMA is administered at ambient temperatures of 24°C or greater, 68 and the degree of hyperthermia positively correlates with increasing ambient temperature 69,70 .…”

Section: Sympathomimetic-induced Hyperthermiamentioning

confidence: 99%

The heat is on: Molecular mechanisms of drug-induced hyperthermia

2014

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Thermoregulation is an essential homeostatic process in which critical mechanisms of heat production and dissipation are controlled centrally in large part by the hypothalamus and peripherally by activation of the sympathetic nervous system. Drugs that disrupt the components of this highly orchestrated multi-organ process can lead to life-threatening hyperthermia. In most cases, hyperthermic agents raise body temperature by increasing the central and peripheral release of thermoregulatory neurotransmitters that ultimately lead to heat production in thermogenic effector organs skeletal muscle (SKM) and brown adipose tissue (BAT). In many cases hyperthermic drugs also decrease heat dissipation through peripheral changes in blood flow. Drug-induced heat production is driven by the stimulation of mechanisms that normally regulate the adaptive thermogenic responses including both shivering and non-shivering thermogenesis (NST) mechanisms. Modulation of the mitochondrial electrochemical proton/pH gradient by uncoupling protein 1 (UCP1) in BAT is the most well characterized mechanism of NST in response to cold, and may contribute to thermogenesis induced by sympathomimetic agents, but this is far from established. However, the UCP1 homologue, UCP3, and the ryanodine receptor (RYR1) are established mediators of toxicant-induced hyperthermia in SKM. Defining the molecular mechanisms that orchestrate drug-induced hyperthermia will be essential in developing treatment modalities for thermogenic illnesses. This review will briefly summarize mechanisms of thermoregulation and provide a survey of pharmacologic agents that can lead to hyperthermia. We will also provide an overview of the established and candidate molecular mechanisms that regulate the actual thermogenic processes in heat effector organs BAT and SKM.

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Strenuous exercise aggravates MDMA-induced skeletal muscle damage in mice

Cited by 19 publications

References 27 publications

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

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

Potentiation of Ecstasy-induced hyperthermia and FAT/CD36 expression in chronically exercised animals

The heat is on: Molecular mechanisms of drug-induced hyperthermia

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