Lipid metabolism drives allele-specific early-stage hypertrophic cardiomyopathy

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