Multi-Omics Approach Profiling Metabolic Remodeling in Early Systolic Dysfunction and in Overt Systolic Heart Failure

Antoine H Chaanine; LeeAnn Higgins; Todd Markowski; Jarrod Harman; Maureen Kachman; Charles Burant; L Gabriel Navar; David Busija; Patrice Delafontaine

doi:10.3390/ijms23010235

Multi-Omics Approach Profiling Metabolic Remodeling in Early Systolic Dysfunction and in Overt Systolic Heart Failure

Int J Mol Sci. 2021 Dec 26;23(1):235. doi: 10.3390/ijms23010235.

Authors

Antoine H Chaanine^{1

2}, LeeAnn Higgins³, Todd Markowski³, Jarrod Harman⁴, Maureen Kachman⁵, Charles Burant⁶, L Gabriel Navar², David Busija^{7

8}, Patrice Delafontaine^{1

2

7}

Affiliations

¹ Department of Medicine, Tulane University, New Orleans, LA 70112, USA.
² Department of Physiology, Tulane University, New Orleans, LA 70112, USA.
³ Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
⁴ Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
⁵ Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁷ Department of Pharmacology, Tulane University, New Orleans, LA 70112, USA.
⁸ Tulane Brain Institute, Tulane University, New Orleans, LA 70112, USA.

Abstract

Metabolic remodeling plays an important role in the pathophysiology of heart failure (HF). We sought to characterize metabolic remodeling and implicated signaling pathways in two rat models of early systolic dysfunction (MOD), and overt systolic HF (SHF). Tandem mass tag-labeled shotgun proteomics, phospho-(p)-proteomics, and non-targeted metabolomics analyses were performed in left ventricular myocardium tissue from Sham, MOD, and SHF using liquid chromatography-mass spectrometry, n = 3 biological samples per group. Mitochondrial proteins were predominantly down-regulated in MOD (125) and SHF (328) vs. Sham. Of these, 82% (103/125) and 66% (218/328) were involved in metabolism and respiration. Oxidative phosphorylation, mitochondrial fatty acid β-oxidation, Krebs cycle, branched-chain amino acids, and amino acid (glutamine and tryptophan) degradation were highly enriched metabolic pathways that decreased in SHF > MOD. Glycogen and glucose degradation increased predominantly in MOD, whereas glycolysis and pyruvate metabolism decreased predominantly in SHF. PKA signaling at the endoplasmic reticulum-mt interface was attenuated in MOD, whereas overall PKA and AMPK cellular signaling were attenuated in SHF vs. Sham. In conclusion, metabolic remodeling plays an important role in myocardial remodeling. PKA and AMPK signaling crosstalk governs metabolic remodeling in progression to SHF.

Keywords: AMPK; PKA; calcium cycling; heart failure; metabolic remodeling; mitochondria.

MeSH terms

Adenylate Kinase / metabolism
Animals
Chromatography, Liquid
Citric Acid Cycle
Cyclic AMP-Dependent Protein Kinases / metabolism
Glycolysis
Heart Failure, Systolic / metabolism*
Mass Spectrometry
Metabolic Networks and Pathways*
Metabolomics*
Mitochondria / metabolism
Oxidative Phosphorylation
Rats
Signal Transduction

Substances

Cyclic AMP-Dependent Protein Kinases
Adenylate Kinase

Abstract

MeSH terms

Substances

Grants and funding