Metabolic Alterations in Cardiomyocytes are Associated with Methamphetamine‐Induced Cardiomyopathy

Abstract

IntroductionIllicit use of Methamphetamine (METH) in humans is associated with cardiac dysfunction known as METH‐induced cardiomyopathy. Specifically, the stimulant inhibits mitochondrial bioenergetics, resulting in energy deprivation, which may ultimately lead to the activation of the adaptive autophagy process.ObjectivesWe aim to determine the METH‐induced metabolic alterations in cardiomyocytes leading to the development of the METH‐associated cardiomyopathy.Methods and ResultsAutopsy heart samples from humans with a positive toxicology for METH use showed substantial fibrosis in the heart. ‘Binge’ METH‐administration in mice for four weeks developed cardiac hypertrophy and fibrosis in the heart. Mitochondria isolated from the METH‐treated heart showed defects in mitochondrial respiration. Western blot analysis of autophagy regulatory protein expression ‘Binge’ METH‐treated mice showed increased expression of LC3B‐II and p62 proteins. To determine the direct non‐catecholamine dependent effect of METH on cardiomyocytes, we treated primary cardiomyocytes with different doses of METH (100 and 250 μM). Western Blot analysis showed a dose and time‐dependent increase in the expression of LC3B‐II and autophagy‐related protein 7 (Atg7). We also observed increased phosphorylation of cellular metabolism‐related proteins, i.e., phosphorylated FOXO1 (at Ser 256) and FOXO3a (at Ser 253). We conducted autophagy flux assay to confirm the METH‐induced activation of autophagy exposing cardiomyocytes with METH (250 μM for 24 hours) followed by treatment with lysosomal inhibitor BafilomycinA1 (50nM for 3 hours). Western Blot analysis showed increased expression of LC3B‐II in BafA1 treated cardiomyocytes suggesting activation of autophagy following METH‐exposure.ConclusionsWe report that METH use causes adverse fibrotic remodeling in hearts from both human and pre‐clinical mouse model. We found that METH suppresses mitochondrial respiration in cardiomyocytes that elicit adaptive activation of autophagy and autophagy regulatory proteins as a response to METH‐induced energy deprivation.Support or Funding InformationThis project was performed as part of the CURIOUS program supported by grant R25HL147665 from the NIH/NHLBI. This work was further supported by NIH/NHLBI grants R00 HL122354, R01HL145753, R01HL145753‐01S1 and PGM121307A to Dr. Bhuiyan. American Heart Association postdoctoral fellowship to Dr. Alam; Malcolm Fiest post‐ and pre‐doctoral fellowships to Dr. Abdullah and Aishwarya by CCDS, LSUHSC‐S.