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Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth
Journal article   Open access   Peer reviewed

Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth

Andrew A Gibb, Paul N Epstein, Shizuka Uchida, Yuting Zheng, Lindsey A McNally, Detlef Obal, Kartik Katragadda, Patrick Trainor, Daniel J Conklin, Kenneth R Brittian, …
Circulation (New York, N.Y.), Vol.136(22), pp.2144-2157
11/28/2017
DOI: 10.1161/CIRCULATIONAHA.117.028274
PMCID: PMC5704654
PMID: 28860122
url
https://doi.org/10.1161/CIRCULATIONAHA.117.028274View
Published (Version of record) Open Access

Abstract

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. 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. 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 mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of Glyco 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 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. Exercise-induced decreases in glycolytic activity stimulate physiological cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart.
 Mutation Phenotype Adaptation, Physiological Animals Cardiomegaly, Exercise-Induced Exercise Tolerance Fatty Acids - metabolism Gene Expression Profiling - methods Gene Expression Regulation Genotype Glucose - metabolism Glycolysis - genetics Heart - growth & development Isolated Heart Preparation Male Metabolomics - methods Mice, Transgenic Mitochondria, Heart - metabolism Mitochondria, Heart - ultrastructure Myocardium - metabolism Myocardium - ultrastructure Phosphofructokinase-2 - genetics Phosphofructokinase-2 - metabolism Physical Exertion Running Time Factors Transcriptome Ventricular Remodeling

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