Western diet triggers cardiac dysfunction in heterozygous Mybpc3-targeted knock-in mice: a two-hit model of hypertrophic cardiomyopathy

  • Edgar E. Nollet
  • Sila Algül
  • Max Goebel
  • Saskia Schlossarek
  • Nicole N. van der Wel
  • Judith J. M. Jans
  • Mark A. van de Wiel
  • Jaco C. Knol
  • Thang C. Pham
  • Sander R. Piersma
  • Richard de Goeij-de Haas
  • Jill Hermans
  • Jan Bert van Klinken
  • Michel van Weeghel
  • Riekelt H. Houtkooper
  • Lucie Carrier
  • Connie R. Jimenez
  • Diederik W. D. Kuster
  • Jolanda van der Velden

Abstract

Background and aim: Phenotypic expression of hypertrophic cardiomyopathy (HCM) and disease course are associated with unfavorable metabolic health. We investigated if Western diet (WD) feeding is sufficient to trigger cardiac hypertrophy and dysfunction in heterozygous (HET) Mybpc3c.772G>A knock-in mice.
Methods and results: Wild-type (WT) and HET mice (3-months-old) were fed a WD or normal chow (NC) for 8 weeks. Metabolomic analyses on serum revealed systemic metabolic derailment in WD-fed WT and HET mice. Strikingly, only WD-fed HET mice developed cardiac hypertrophy and dysfunction, which was not driven by aggravated cardiac myosin binding protein-C haploinsufficiency. WD reduced oxidative phosphorylation and increased toxic lipids in the heart irrespective of genotype. Cardiac proteomic analyses revealed higher abundance
of proteins involved in fatty acid oxidation in WD-fed mice, however this increase was blunted in HET compared to WT mice. Accordingly, cardiac metabolomic and lipidomic analyses showed accumulation of acylcarnitines in WD-fed HET vs WT mice.
Conclusion: WD feeding triggered cardiac dysfunction and hypertrophy in otherwise phenotype-negative HET Mybpc3c.772G>A mice. We propose that the presence of a HCM mutation predisposes the heart to metabolic inflexibility when subjected to systemic metabolic stress. Our study represents a novel approach to study the interplay between unfavorable metabolic health and mutation-induced defects in HCM disease development.

Bibliografische Daten

OriginalspracheEnglisch
Aufsatznummer100050
ISSN2772-9761
DOIs
StatusVeröffentlicht - 19.11.2023