Abdurrachim 2014 Biochim Biophys Acta

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Abdurrachim D, Ciapaite J, Wessels B, Nabben M, Luiken JJ, Nicolay K, Prompers JJ (2014) Cardiac diastolic dysfunction in high-fat diet fed mice is associated with lipotoxicity without impairment of cardiac energetics in vivo. Biochim Biophys Acta 1842:1525-37.

» PMID: 25086219

Abdurrachim D, Ciapaite J, Wessels B, Nabben M, Luiken JJ, Nicolay K, Prompers JJ (2014) Biochim Biophys Acta

Abstract: Obesity is often associated with abnormalities in cardiac morphology and function. This study tested the hypothesis that obesity-related cardiomyopathy is caused by impaired cardiac energetics. In a mouse model of high-fat diet (HFD)-induced obesity, we applied in vivo cardiac 31P magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) to investigate cardiac energy status and function, respectively. The measurements were complemented by ex vivo determination of oxygen consumption in isolated cardiac mitochondria, the expression of proteins involved in energy metabolism, and markers of oxidative stress and calcium homeostasis. We also assessed whether HFD induced myocardial lipid accumulation using in vivo 1H MRS, and if this was associated with apoptosis and fibrosis. Twenty weeks of HFD feeding resulted in early stage cardiomyopathy, as indicated by diastolic dysfunction and increased left ventricular mass, without any effects on systolic function. In vivo cardiac phosphocreatine-to-ATP ratio and ex vivo oxygen consumption in isolated cardiac mitochondria were not reduced after HFD feeding, suggesting that the diastolic dysfunction was not caused by impaired cardiac energetics. HFD feeding promoted mitochondrial adaptations for increased utilization of fatty acids, which was however not sufficient to prevent the accumulation of myocardial lipids and lipid intermediates. Myocardial lipid accumulation was associated with oxidative stress and fibrosis, but not apoptosis. Furthermore, HFD feeding strongly reduced the phosphorylation of phospholamban, a prominent regulator of cardiac calcium homeostasis and contractility. In conclusion, HFD-induced early stage cardiomyopathy in mice is associated with lipotoxicity-associated oxidative stress, fibrosis, and disturbed calcium homeostasis, rather than impaired cardiac energetics.

Keywords: Calcium homeostasis, Cardiac energetics, Cardiomyopathy, Diet-induced obesity, Lipotoxicity

O2k-Network Lab: NL Eindhoven Nicolay K, NL Groningen Reijngoud RJ, NL Maastricht Schrauwen P


Labels: MiParea: Respiration, Exercise physiology;nutrition;life style  Pathology: Obesity 

Organism: Mouse  Tissue;cell: Heart  Preparation: Isolated mitochondria 


Coupling state: LEAK, OXPHOS, ET  Pathway: F, N  HRR: Oxygraph-2k