Metabolic alterations in a rat model of takotsubo syndrome.

Godsman, Nadine; Kohlhaas, Michael; Nickel, Alexander; Cheyne, Lesley; Mingarelli, Marco; Schweiger, Lutz; Hepburn, Claire; Munts, Chantal; Welch, Andy; Delibegovic, Mirela; Bilsen, Marc Van; Maack, Christoph; Dawson, Dana K.

Abstract

Cardiac energetic impairment is a major finding in takotsubo patients. We investigate specific metabolic adaptations to direct future therapies. An isoprenaline-injection female rat model (vs. sham) was studied at Day 3; recovery assessed at Day 7. Substrate uptake, metabolism, inflammation, and remodelling were investigated by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography, metabolomics, quantitative PCR, and western blot (WB). Isolated cardiomyocytes were patch-clamped during stress protocols for redox states of NAD(P)H/FAD or [Ca2+]c, [Ca2+]m, and sarcomere length. Mitochondrial respiration was assessed by seahorse/Clark electrode (glycolytic and β-oxidation substrates). Cardiac 18F-FDG metabolic rate was increased in takotsubo (P = 0.006), as was the expression of GLUT4-RNA/GLUT1/HK2-RNA and HK activity (all P < 0.05), with concomitant accumulation of glucose-and fructose-6-phosphates (P > 0.0001). Both lactate and pyruvate were lower (P < 0.05) despite increases in LDH-RNA and PDH (P < 0.05 both). β-Oxidation enzymes CPT1b-RNA and 3-ketoacyl-CoA thiolase were increased (P < 0.01) but malonyl-CoA (CPT-1 regulator) was upregulated (P = 0.01) with decreased fatty acids and acyl-carnitines levels (P = 0.0001-0.02). Krebs cycle intermediates α-ketoglutarate and succinyl-carnitine were reduced (P < 0.05) as was cellular ATP reporter dihydroorotate (P = 0.003). Mitochondrial Ca2+ uptake during high workload was impaired on Day 3 (P < 0.0001), inducing the oxidation of NAD(P)H and FAD (P = 0.03) but resolved by Day 7. There were no differences in mitochondrial respiratory function, sarcomere shortening, or [Ca2+] transients of isolated cardiomyocytes, implying preserved integrity of both mitochondria and cardiomyocyte. Inflammation and remodelling were upregulated-increased CD68-RNA, collagen RNA/protein, and skeletal actin RNA (all P < 0.05). Dysregulation of glucose and lipid metabolic pathways with decreases in final glycolytic and β-oxidation metabolites and reduced availability of Krebs intermediates characterizes takotsubo myocardium. The energetic deficit accompanies defective Ca2+ handling, inflammation, and upregulation of remodelling pathways, with the preservation of sarcomeric and mitochondrial integrity.

Citation

GODSMAN, N., KOHLHASS, M., NICKEL, A., CHEYNE, L., MINGARELLI, M., SCHWEIGHER, L., HEPBURN, C., MUNTS, C., WELCH, A., DELIBEGOVIC, M., BILSEN, M. VAN., MAACK, C. and DAWSON, D.K. 2022. Metabolic alterations in a rat model of takotsubo syndrome. Cardiovascular research [online], 118(8), pages 1932-1946. Available from: https://doi.org/10.1093/cvr/cvab081

• Journal Article Type: Article
• Acceptance Date: Mar 9, 2021
• Online Publication Date: Mar 12, 2021
• Publication Date: May 31, 2022
• Deposit Date: Oct 15, 2024
• Publicly Available Date: Oct 15, 2024
• Journal: Cardiovascular research
• Print ISSN: 0008-6363
• Electronic ISSN: 1755-3245
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 118
• Issue: 8
• Pages: 1932-1946
• DOI: https://doi.org/10.1093/cvr/cvab081
• Keywords: Takotsubo; Metabolism; Energetics; Inflammation; Remodelling; Heart failure
• Public URL: https://rgu-repository.worktribe.com/output/2516332
• Additional Information: This article has been published with separate supporting information. This supporting information has been incorporated into a single file on this repository and can be found at the end of the file associated with this output.