Non-targeted metabolomics of double-mutant cardiomyocytes reveals a novel role for SWI/SNF complexes in metabolic homeostasis.

Mammalian SWI/SNF chromatin-remodeling complexes utilize either BRG1 or as alternative catalytic subunits to alter the position of nucleosomes and regulate gene expression. Genetic studies have demonstrated that SWI/SNF complexes are required during cardiac development and also protect against cardiovascular disease and cancer. However, constitutive null mutants do not exhibit a cardiomyocyte phenotype and inducible conditional mutations in cardiomyocyte do not demonstrate differences until stressed with transverse aortic constriction, where they exhibit a reduction in cardiac hypertrophy. We recently demonstrated the overlapping functions of and in vascular endothelial cells and sought here to test if this overlapping function occurred in cardiomyocytes. double mutants died within 21 days of severe cardiac dysfunction associated with glycogen accumulation and mitochondrial defects based on histological and ultrastructural analyses. To determine the underlying defects, we performed nontargeted metabolomics analysis of cardiac tissue by GC/MS from a line of double-mutant mice, which lack both and in cardiomyocytes in an inducible manner, and two groups of controls. Metabolites contributing most significantly to the differences between double-mutant and control-group hearts were then determined using the variable importance in projection analysis. Increased cardiac linoleic acid and oleic acid suggest alterations in fatty acid utilization or intake are perturbed in double mutants. Conversely, decreased glucose-6-phosphate, fructose-6-phosphate, and myoinositol suggest that glycolysis and glycogen formation are impaired. These novel metabolomics findings provide insight into SWI/SNF-regulated metabolic pathways and will guide mechanistic studies evaluating the role of SWI/SNF complexes in homeostasis and cardiovascular disease prevention.