Fructose diet treatment in mice induces fundamental disturbance of cardiomyocyte Ca²⁺handling and myofilament responsiveness

Abstract

Mellor KM, Wendt IR, Ritchie RH, Delbridge LM. Fructose diet treatment in mice induces fundamental disturbance of cardiomyocyte Ca 2ϩ handling and myofilament responsiveness. Am J Physiol Heart Circ Physiol 302: H964 -H972, 2012. First published December 23, 2011; doi:10.1152/ajpheart.00797.2011.-High fructose intake has been linked to insulin resistance and cardiac pathology. Dietary fructose-induced myocardial signaling and morphological alterations have been described, but whether cardiomyocyte function is influenced by chronic high fructose intake is yet to be elucidated. The goal of this study was to evaluate the cardiomyocyte excitationcontraction coupling effects of high dietary fructose and determine the capacity for murine cardiomyocyte fructose transport. Male C57Bl/6J mice were fed a high fructose diet for 12 wk. Fructose-and controlfed mouse cardiomyocytes were isolated and loaded with the fura 2 ) was reduced, and protein phosphatase 2A expression increased, in fructosefed mouse hearts. Hypertension and cardiac hypertrophy were not evident. These findings demonstrate that fructose diet-associated myocardial insulin resistance induces profound disturbance of cardiomyocyte Ca 2ϩ handling and responsiveness in the absence of altered systemic loading conditions. excitation-contraction coupling; cardiac; myocardial; cellular IN WESTERN SOCIETIES, the use of added sweeteners has increased by 25% during the last 30 years, and it has been estimated that the average adolescent (North American) consumes over 30% of energy intake in the form of added sugars (17,29). Fructose intake has been identified as a significant risk factor for insulin resistance and cardiovascular disease, independent of body mass index (45). Experimental models have demonstrated that a high fructose diet disturbs metabolic homeostasis, increases plasma fructose, and induces systemic insulin resistance in rodents (2,24,32,35). The existence of an insulin-resistant cardiomyopathy, associated with perturbed cardiac metabolism and functional impairment, is generally recognized (33,46,48). In a previous study, we have demonstrated that excess fructose intake is associated with elevated blood glucose, glucose intolerance, and normal plasma insulin in the absence of hypertension and obesity (35). We have also shown that fructose feeding induces diffuse myocardial fibrotic infiltration linked with suppressed cardiomyocyte viability signaling (35). The impact of elevated dietary fructose intake on cardiomyocyte functional performance is yet to be demonstrated.Cellular fructose uptake is mediated by insulin-independent transporters. Fructose is rapidly phosphorylated by fructokinase and bypasses the glycolytic rate-limiting enzyme, phosphofructokinase, proceeding through glycolysis to produce pyruvate and lactate in a less-controlled manner than glucose (30). The close association of glycolytic enzymes with Ca 2ϩ -related transporters provides indication that specific excitationcontraction coupling processes are particularly reliant on glycolyt...

Focal but reversible diastolic sheet dysfunction reflects regional calcium mishandling in dystrophicmdxmouse hearts

“…Because the calcium relaxation process is not monoexponential, only the latter half of the calcium signal decay could be fitted exponentially to derive the decay constant. Typically, both 50% relaxation decay time (T50) and the decay constant are used to characterize calcium relaxation kinetics (12,29,47,48,57,58,64,72,75,80). Specifically, the Ca 2ϩ relaxation time from the calcium transient peak value to 50% relaxation (T50) was calculated to define the calcium reuptake phase, and Ca 2ϩ decay constant was calculated using an exponential curve fitting program from the 50% calcium peak value to full relaxation.…”

Abnormal amounts of intracellular calcium regulatory proteins in SHRSP.Z-Leprfa/IzmDmcr rats with metabolic syndrome and cardiac dysfunction

“…Thus, changes in the amounts of these intracellular Ca 2+ regulatory proteins, leading to abnormal intracellular Ca 2+ homeostasis, are relevant to cardiac muscle physiology and pathology (Periasamy et al 2008;Glaves et al 2011). However, there is still controversy as to whether SERCA and PLB protein amounts are altered in lifestyle-related diseases with cardiac dysfunction (Boknik et al 2001;Sande et al 2002;Zhong et al 2003;Li et al 2005;Relling et al 2006;Connelly et al 2007;Yao et al 2009;Ceylan-Isik et al 2011;Rodrigues et al 2011;Bai et al 2012;Dupont et al 2012;Mellor et al 2012;Miklos et al 2012). Furthermore, although PLB is known to exist in oligomeric and monomeric forms, with the monomeric form being the active species that regulates Ca 2+ transport (Periasamy et al 2008), there have been few studies of changes in the amount of each form in disease conditions.…”

Update on innovative initiatives for the American Journal of Physiology-Heart and Circulatory Physiology

“…Particular highlights include a podcast on the work by Cabrera et al (12) in which we delved deeper into the protective effects of ischemic preconditioning and the phenomenon dubbed the second window of protection. Regarding the work by Mellor et al (60) on diabetic cardiomyopathy, we explored how a high-fructose diet has profound effects on myocyte Ca 2ϩ handling. In a spirited podcast interview about the comprehensive review by Poole et al (72), we unpacked the complexities of exercise intolerance in heart failure patients at the oxygen transport and microcirculatory levels.…”

“…Muscle mechanics and ventricular function played a key role in our highlighted articles and editorial podcasts (28, 54,60). The work by Wang et al (102) offered the opportunity to explore the role of phospholemman at the molecular level as well as how the regulation of sodium-calcium exchange by phospholemman may affect cardiac stress responses, such as fight or flight.…”

“…Regarding the work by Mellor et al (60) on diabetic cardiomyopathy, we explored how a high-fructose diet has profound effects on myocyte Ca 2ϩ handling. In a spirited podcast interview about the comprehensive review by Poole et al (72), we unpacked the complexities of exercise intolerance in heart failure patients at the oxygen transport and microcirculatory levels.Muscle mechanics and ventricular function played a key role in our highlighted articles and editorial podcasts (28,54,60). The work by Wang et al (102) offered the opportunity to explore the role of phospholemman at the molecular level as well as how the regulation of sodium-calcium exchange by phospholemman may affect cardiac stress responses, such as fight or flight.…”