Glucose transporter 4-deficient hearts develop maladaptive hypertrophy in response to physiological or pathological stresses

Abstract

Pathological cardiac hypertrophy may be associated with reduced expression of glucose transporter 4 (GLUT4) in contrast to exercise-induced cardiac hypertrophy, where GLUT4 levels are increased. However, mice with cardiac-specific deletion of GLUT4 (G4H) have normal cardiac function in the unstressed state. This study tested the hypothesis that cardiac GLUT4 is required for myocardial adaptations to hemodynamic demands. G4H and control littermates were subjected to either a pathological model of left ventricular pressure overload [transverse aortic constriction (TAC)] or a physiological model of endurance exercise (swim training). As predicted after TAC, G4H mice developed significantly greater hypertrophy and more severe contractile dysfunction. Somewhat surprisingly, after exercise training, G4H mice developed increased fibrosis and apoptosis that was associated with dephosphorylation of the prosurvival kinase Akt in concert with an increase in protein levels of the upstream phosphatase protein phosphatase 2A (PP2A). Exercise has been shown to decrease levels of ceramide; G4H hearts failed to decrease myocardial ceramide in response to exercise. Furthermore, G4H hearts have reduced levels of the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1, lower carnitine palmitoyl-transferase activity, and reduced hydroxyacyl-CoA dehydrogenase activity. These basal changes may also contribute to the impaired ability of G4H hearts to adapt to hemodynamic stresses. In conclusion, GLUT4 is required for the maintenance of cardiac structure and function in response to physiological or pathological processes that increase energy demands, in part through secondary changes in mitochondrial metabolism and cellular stress survival pathways such as Akt. Glucose transporter 4 (GLUT4) is required for myocardial adaptations to exercise, and its absence accelerates heart dysfunction after pressure overload. The requirement for GLUT4 may extend beyond glucose uptake to include defects in mitochondrial metabolism and survival signaling pathways that develop in its absence. Therefore, GLUT4 is critical for responses to hemodynamic stresses.

Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity

“…In this context, one possible mechanism is the compromised GLUT4 translocation. Previous studies showed that GLUT4 is an important mediator of enhanced glycolysis and maintaining ATP concentration under various pathological conditions, including IRI [2,8,9,12]. However, significant decreases in the sarcolemmal GLUT4 expression were observed in insulinresistant obese mouse hearts [13,14], consistent with the present findings.…”

“…GLUT4 resides mainly in the intracellular vesicles under basal conditions and is translocated to the plasma membrane in response to insulin as well as other pathological processes, such as ischemic insult. It was previously reported that GLUT4-mediated enhanced glucose transport represents an essential protective mechanism against IRI and other pathological stresses [2,8,9,11,12]. However, it was also reported that the cardiac GLUT4 expression is decreased under insulin-resistant conditions, such as diabetes, in association with the reduction in glucose uptake, leading to impaired glucose utilization in the heart [10,13,14].…”

“…Although the regulation and the functional roles of GLUTs in the heart have been intensively investigated in a variety of in vitro and in vivo models [2,8,9,[12][13][14][15], less is known about the role and functional significance of SGLTs in the heart, particularly under insulin-resistant conditions. In the heart, SGLT1, not SGLT2, is considered to be the dominant isoform [16][17][18].…”

Lipidomic Profiles of the Heart and Circulation in Response to Exercise versus Cardiac Pathology: A Resource of Potential Biomarkers and Drug Targets

“…Increased ceramide (a well-studied sphingolipid) has been linked with cardiac disease and/or pathology in humans and rodents (Chokshi et al, 2012;Havulinna et al, 2016;Ji et al, 2017;Sapra et al, 2014;Yu et al, 2015). In contrast, reduced cardiac ceramide was reported in exercise-trained rodents (Baranowski et al, 2008;Liu et al, 2009;Wende et al, 2017). In the current study, ceramides (as a class) were not decreased in the hearts of swimming mice but tended to be lower ( Figure 3C).…”

Metabolic phenotyping of the pressure-overloaded heart

“…On the other hand, mice with cardiac-specific GLUT4 deletion developed significantly greater hypertrophy and more severe contractile dysfunction after TAC compared to their wild-type littermates. 95 This latter study suggests that GLUT4 may be required (and therefore more important than GLUT1) for maintenance of cardiac structure and function in response to PO.…”