title: Non-targeted metabolomics ofBrg1/Brmdouble-mutant cardiomyocytes reveals a novel role for SWI/SNF complexes in metabolic homeostasis.
abstract: Mammalian SWI/SNF chromatin-remodeling complexes utilize either BRG1 orBrmas 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,Brmconstitutive null mutants do not exhibit a cardiomyocyte phenotype and inducibleBrg1conditional 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 ofBrmandBrg1in vascular endothelial cells and sought here to test if this overlapping function occurred in cardiomyocytes.Brg1/Brmdouble 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 ofBrg1/Brmdouble-mutant mice, which lack bothBrg1andBrmin cardiomyocytes in an inducible manner, and two groups of controls. Metabolites contributing most significantly to the differences betweenBrg1/Brmdouble-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 inBrg1/Brmdouble 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.
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Ranjan
authors.initials: R
authors.lastname: Banerjee
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Bultman
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Darcy
authors.initials: D
authors.lastname: Holley
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Hillhouse
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA. Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Bain
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA. Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Muehlbauer
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA. McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
keywords: BRG1; BRM; Cardiomyocyte; Fatty acid; Glucose; Metabolomics; SWI/SNF complex