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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number235
JournalInternational journal of molecular sciences
Volume23
Issue number1
DOIs
StatePublished - Jan 1 2022

Bibliographical note

Funding Information:
Funding: This work was supported by an internal grant award to A.H.C., and the Carol Lavin Bernick Faculty Grant award to A.H.C.; an NIH/NHLBI R01-HL070241 grant award to P.D.; NIH HL-148836, and NIH AG-063345 grant awards to D.W.B., and the Louisiana Board of Regents Endowed Chairs for Eminent Scholars program to D.W.B.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • AMPK
  • Calcium cycling
  • Heart failure
  • Metabolic remodeling
  • Mitochondria
  • PKA

PubMed: MeSH publication types

  • Journal Article

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