Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth

Abstract

Background Exercise promotes metabolic remodeling in the heart, which is associated with physiologic 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 physiologic 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 (PFK2) 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, upon exercise adaptation and recovery there was an increase in myocardial phosphofructokinase activity and glycolysis. Cardiac-specific expression of a kinase-deficient PFK2 transgene (GlycoLo mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of GlycoLo mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient PFK2 in the heart (GlycoHi mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiologic 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 physiologic cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart.

Altered mitochondrial metabolism in the insulin‐resistant heart

“…Several studies have investigated the cardiometabolic effects of treadmill‐running or swim‐training in rodents . It is commonly reported that training increases myocardial FAO capacity in rodents . Moreover, swim‐training in mice increased cardiac citrate synthase (CS) activity (a putative marker of mitochondrial density) alongside increased PGC‐1α expression .…”

“…238 It is commonly reported that training increases myocardial FAO capacity in rodents. [239][240][241][242][243][244] Moreover, swim-training in mice increased cardiac citrate synthase (CS) activity (a putative marker of mitochondrial density 245 ) alongside increased PGC-1α expression. 244 Of note, moderate intensity training (MIT) elicited different effects to high-intensity interval training (HIIT) in mice when treadmill-running at matched distances.…”

Metabolism

“…A new paper by Gibb et al . in this issue 9 sheds some new light on this question: by using mice with cardiac-specific up- or down-regulation of glycolysis, the authors demonstrate that manipulation of glycolysis alone is capable of inducing cardiac structural, metabolic and functional alterations that mimic the effects of exercise training.…”

“…9 makes an important link between several aspects of exercise-induced hypertrophy and alterations in metabolism. These findings strengthen the notion that metabolism is an important driver of the hypertrophic phenotype.…”

Metabolic regulation of myocardial adaptation to exercise.

“…The three salient findings from our studies, related to the heart, are: (1) that periodic decreases in myocardial glycolytic activity are sufficient to promote physiologic cardiac growth 304 ; (2) that maintenance of metabolic flexibility in the heart is essential for mitochondrial health 304 ; and (3) that glycolytic activity in cardiomyocytes coordinates the biosynthesis of nucleotides, nucleotide sugars, and glycero(phospho)lipids. 305 Our findings have several implications, germane to both the basic understanding of cardiac remodeling as well as future targets for therapy.…”