Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth.

Autor:	Gibb AA; Institute of Molecular Cardiology (A.A.G., Y.Z., L.A.M., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.).; Diabetes and Obesity Center (A.A.G., Y.Z., L.A.M., D.O., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.).; Department of Physiology (A.A.G., B.G.H.)., Epstein PN; Department of Pediatrics (P.N.E.)., Uchida S; Cardiovascular Innovation Institute (S.U.)., Zheng Y; Institute of Molecular Cardiology (A.A.G., Y.Z., L.A.M., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.).; Diabetes and Obesity Center (A.A.G., Y.Z., L.A.M., D.O., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.)., McNally LA; Institute of Molecular Cardiology (A.A.G., Y.Z., L.A.M., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.).; Diabetes and Obesity Center (A.A.G., Y.Z., L.A.M., D.O., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.)., Obal D; Diabetes and Obesity Center (A.A.G., Y.Z., L.A.M., D.O., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.).; Department of Anesthesiology (D.O.)., Katragadda K; Institute of Molecular Cardiology (A.A.G., Y.Z., L.A.M., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.).; Diabetes and Obesity Center (A.A.G., Y.Z., L.A.M., D.O., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.)., Trainor P; Institute of Molecular Cardiology (A.A.G., Y.Z., L.A.M., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.).; Diabetes and Obesity Center (A.A.G., Y.Z., L.A.M., D.O., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.)., Conklin DJ; Institute of Molecular Cardiology (A.A.G., Y.Z., L.A.M., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.).; Diabetes and Obesity Center (A.A.G., Y.Z., L.A.M., D.O., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.)., Brittian KR; Institute of Molecular Cardiology (A.A.G., Y.Z., L.A.M., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.).; Diabetes and Obesity Center (A.A.G., Y.Z., L.A.M., D.O., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.)., Tseng MT; Department of Anatomy and Neuroscience (M.T.T.)., Wang J; University of Louisville, KY. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (J.W.)., Jones SP; Institute of Molecular Cardiology (A.A.G., Y.Z., L.A.M., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.).; Diabetes and Obesity Center (A.A.G., Y.Z., L.A.M., D.O., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.)., Bhatnagar A; Institute of Molecular Cardiology (A.A.G., Y.Z., L.A.M., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.).; Diabetes and Obesity Center (A.A.G., Y.Z., L.A.M., D.O., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.)., Hill BG; Institute of Molecular Cardiology (A.A.G., Y.Z., L.A.M., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.) bradford.hill@louisville.edu.; Diabetes and Obesity Center (A.A.G., Y.Z., L.A.M., D.O., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.).; Department of Physiology (A.A.G., B.G.H.).
Jazyk:	angličtina
Zdroj:	Circulation [Circulation] 2017 Nov 28; Vol. 136 (22), pp. 2144-2157. Date of Electronic Publication: 2017 Aug 31.
DOI:	10.1161/CIRCULATIONAHA.117.028274
Abstrakt:	Background: Exercise promotes metabolic remodeling in the heart, which is associated with physiological cardiac growth; however, it is not known whether or how physical activity-induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiological cardiac growth. Methods: We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart. Results: Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, in the recovered state following exercise adaptation, there was an increase in myocardial phosphofructokinase activity and glycolysis. In mice, cardiac-specific expression of a kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgene (Glyco Lo mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of Glyco Lo mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in the heart (Glyco Hi mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiological cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose-fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling. Conclusions: Exercise-induced decreases in glycolytic activity stimulate physiological cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart. (© 2017 The Authors.)
Databáze:	MEDLINE
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