Key result
Methamphetamine self-administration drives pathological cardiac remodeling and mitochondrial dysfunction in preclinical models.
Why the study?
Preclinical studies and animal models to dissect detailed molecular mechanisms of methamphetamine-associated cardiomyopathy development are scarce.
Answers are grounded in this paper and cite their sources.
Rat self-administration data suggest mitochondrial-autophagy mechanisms in methamphetamine cardiomyopathy; leaves open human translation and therapeutic targeting.
The recent rise in illicit use of methamphetamine (METH), a highly addictive psychostimulant, is a huge health care burden due to its central and peripheral toxic effects. Mounting clinical studies have noted that METH use in humans is associated with the development of cardiomyopathy; however, preclinical studies and animal models to dissect detailed molecular mechanisms of METH-associated cardiomyopathy development are scarce. The present study utilized a unique very long-access binge and crash procedure of METH self-administration to characterize the sequelae of pathological alterations that occur with METH-associated cardiomyopathy. Rats were allowed to intravenously self-administer METH for 96 h continuous weekly sessions over 8 weeks. Cardiac function, histochemistry, ultrastructure, and biochemical experiments were performed 24 h after the cessation of drug administration. Voluntary METH self-administration induced pathological cardiac remodeling as indicated by cardiomyocyte hypertrophy, myocyte disarray, interstitial and perivascular fibrosis accompanied by compromised cardiac systolic function. Ultrastructural examination and native gel electrophoresis revealed altered mitochondrial morphology and reduced mitochondrial oxidative phosphorylation (OXPHOS) supercomplexes (SCs) stability and assembly in METH exposed hearts. Redox-sensitive assays revealed significantly attenuated mitochondrial respiratory complex activities with a compensatory increase in pyruvate dehydrogenase (PDH) activity reminiscent of metabolic remodeling. Increased autophagy flux and increased mitochondrial antioxidant protein level was observed in METH exposed heart. Treatment with mitoTEMPO reduced the autophagy level indicating the involvement of mitochondrial dysfunction in the adaptive activation of autophagy in METH exposed hearts. Altogether, we have reported a novel METH-associated cardiomyopathy model using voluntary drug seeking behavior. Our studies indicated that METH self-administration profoundly affects mitochondrial ultrastructure, OXPHOS SCs assembly and redox activity accompanied by increased PDH activity that may underlie observed cardiac dysfunction.
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Abdullah et al. (2022) studied Methamphetamine-associated cardiomyopathy. Methamphetamine self-administration vs. Yoked saline control was evaluated on Pathological cardiac remodeling and mitochondrial dysfunction. Voluntary methamphetamine self-administration in rats induced pathological cardiac remodeling, mitochondrial ultrastructural anomalies, reduced oxidative phosphorylation supercomplex stability, and increased autophagy flux.
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