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bioRxiv · 10.1101/2023.11.10.564562

Lipid metabolism drives allele-specific early-stage hypertrophic cardiomyopathy

Vaniya, A.·Karlstaedt, A.·Ates Gulkok, D.·Thottakara, T.·Liu, Y.·Fan, S.·Eades, H.·Fukunaga, R.·Vernon, H. J.·Fiehn, O.·Abraham, M. R.
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Abstract

Hypertrophic cardiomyopathy (HCM) results from pathogenic variants in sarcomeric protein genes, that increase myocyte energy demand and lead to cardiac hypertrophy. But it is unknown whether a common metabolic trait underlies the cardiac phenotype at early disease stage. This study characterized two HCM mouse models (R92W-TnT, R403Q-MyHC) that demonstrate differences in mitochondrial function at early disease stage. Using a combination of cardiac phenotyping, transcriptomics, mass spectrometry-based metabolomics and computational modeling, we discovered allele-specific differences in cardiac structure/function and metabolic changes. TnT-mutant hearts had impaired energy substrate metabolism and increased phospholipid remodeling compared to MyHC-mutants. TnT-mutants showed increased incorporation of saturated fatty acid residues into ceramides, cardiolipin, and increased lipid peroxidation, that could underlie allele-specific differences in mitochondrial function and cardiomyopathy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=172 HEIGHT=200 SRC="FIGDIR/small/564562v1_ufig1.gif" ALT="Figure 1"> O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/564562v1_ufig2.gif" ALT="Figure 1"> O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/564562v1_ufig3.gif" ALT="Figure 1"> View larger version (90K): org.highwire.dtl.DTLVardef@195b1d7org.highwire.dtl.DTLVardef@cead88org.highwire.dtl.DTLVardef@e2bf35org.highwire.dtl.DTLVardef@776765_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Vaniya, A., Karlstaedt, A., Ates Gulkok, D., Thottakara, T., Liu, Y., Fan, S., Eades, H., Fukunaga, R., Vernon, H. J., Fiehn, O., Abraham, M. R.. 2023-11-15. Lipid metabolism drives allele-specific early-stage hypertrophic cardiomyopathy. https://doi.org/10.1101/2023.11.10.564562

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