Cardiac diastolic dysfunction in high-fat diet fed mice is associated with lipotoxicity without impairment of cardiac energetics in vivo

Desiree Abdurrachim, Jolita Ciapaite, Bart Wessels, Miranda Nabben, Joost J. F. P. Luiken, Klaas Nicolay, Jeanine J. Prompers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

43 Citations (Web of Science)

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 P-31 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 H-1 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.
Original languageEnglish
Pages (from-to)1525-1537
JournalBiochimica et Biophysica Acta-Molecular and Cell Biology of Lipids
Volume1841
Issue number10
DOIs
Publication statusPublished - Oct 2014

Keywords

  • Diet-induced obesity
  • Cardiomyopathy
  • Cardiac energetics
  • Lipotcodcity
  • Calcium homeostasis

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