Western diet triggers cardiac dysfunction in heterozygous Mybpc3-targeted knock-in mice: a two-hit model of hypertrophic cardiomyopathy
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Western diet triggers cardiac dysfunction in heterozygous Mybpc3-targeted knock-in mice: a two-hit model of hypertrophic cardiomyopathy. / Nollet, Edgar E.; Algül, Sila; Goebel, Max; Schlossarek, Saskia; van der Wel, Nicole N.; Jans, Judith J. M.; van de Wiel, Mark A.; Knol, Jaco C.; Pham, Thang C.; Piersma, Sander R.; de Goeij-de Haas, Richard; Hermans, Jill; van Klinken, Jan Bert; van Weeghel, Michel; Houtkooper, Riekelt H.; Carrier, Lucie; Jimenez, Connie R.; Kuster, Diederik W. D.; van der Velden, Jolanda.
In: Journal of molecular and cellular cardiology plus, Vol. 6, 100050, 19.11.2023.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Western diet triggers cardiac dysfunction in heterozygous Mybpc3-targeted knock-in mice: a two-hit model of hypertrophic cardiomyopathy
AU - Nollet, Edgar E.
AU - Algül, Sila
AU - Goebel, Max
AU - Schlossarek, Saskia
AU - van der Wel, Nicole N.
AU - Jans, Judith J. M.
AU - van de Wiel, Mark A.
AU - Knol, Jaco C.
AU - Pham, Thang C.
AU - Piersma, Sander R.
AU - de Goeij-de Haas, Richard
AU - Hermans, Jill
AU - van Klinken, Jan Bert
AU - van Weeghel, Michel
AU - Houtkooper, Riekelt H.
AU - Carrier, Lucie
AU - Jimenez, Connie R.
AU - Kuster, Diederik W. D.
AU - van der Velden, Jolanda
PY - 2023/11/19
Y1 - 2023/11/19
N2 - 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 abundanceof 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.
AB - 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 abundanceof 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.
UR - https://www.sciencedirect.com/science/article/pii/S277297612300020X
U2 - 10.1016/j.jmccpl.2023.100050
DO - 10.1016/j.jmccpl.2023.100050
M3 - SCORING: Journal article
VL - 6
JO - Journal of molecular and cellular cardiology plus
JF - Journal of molecular and cellular cardiology plus
SN - 2772-9761
M1 - 100050
ER -