Increased expression of SERCA in the hearts of transgenic mice results in increased oxidation of glucose

Abstract

Dillmann WH. Increased expression of SERCA in the hearts of transgenic mice results in increased oxidation of glucose. Am J Physiol Heart Circ Physiol 292: H1755-H1763, 2007. First published December 1, 2006; doi:10.1152/ajpheart.00884.2006.-While several transgenic mouse models exhibit improved contractile characteristics in the heart, less is known about how these changes influence energy metabolism, specifically the balance between carbohydrate and fatty acid oxidation. In the present study we examine glucose and fatty acid oxidation in transgenic mice, generated to overexpress sarco(endo) plasmic reticulum calcium-ATPase (SERCA), which have an enhanced contractile phenotype. Energy substrate metabolism was measured in isolated working hearts using radiolabeled glucose and palmitate. We also examined oxygen consumption to see whether SERCA overexpression is associated with increased oxygen utilization. Since SERCA is important in calcium handling within the cardiac myocyte, we examined cytosolic calcium transients in isolated myocytes using indo-1, and mitochondrial calcium levels using pericam, an adenovirally expressed, mitochondrially targeted ratiometric calcium indicator. Oxygen consumption did not differ between wildtype and SERCA groups; however, we were able to show an increased utilization of glucose for oxidative metabolism and a corresponding decreased utilization of fatty acids in the SERCA group. Cytosolic calcium transients were increased in myocytes isolated from SERCA mice, and they show a faster rate of decay of the calcium transient. With these observations we noted increased levels of mitochondrial calcium in the SERCA group, which was associated with an increase in the active form of the pyruvate dehydrogenase complex. Since an increase in mitochondrial calcium levels leads to activation of the pyruvate dehydrogenase complex (the rate-limiting step for carbohydrate oxidation), the increased glucose utilization observed in isolated perfused hearts in the SERCA group may reflect a higher level of mitochondrial calcium. mitochondrial calcium; pyruvate dehydrogenase; cardiac energetics; sarco(endo)plasmic reticulum calcium-adenosine 5Ј-triphosphatase IN THE HEART, OXIDATIVE METABOLISM involving ATP production and workload are tightly linked. An increase in cardiac output is associated with an increase in oxygen consumption and an increase in energy substrate metabolism (carbohydrates and fatty acids) (36). An increase in cardiac performance occurs in vivo as a result of increased stimulation by the sympathetic nervous system and can be mimicked in ex vivo isolated heart preparations (Langendorff, working heart) through the use of positive inotropic agents (dobutamine and isoproterenol), an increase in heart rate, an increase in perfusate calcium concentrations, and/or an increase in preload and afterload perfusion pressures (19,23,35,42). The increased cardiac performance is associated with an increased calcium load within the myocyte, affecting the increase in force generation (23). In an att...

Limited functional and metabolic improvements in hypertrophic and healthy rat heart overexpressing the skeletal muscle isoform of SERCA1 by adenoviral gene transfer in vivo

“…We have previously reported that this balance, which is regulated by calcium-sensitive ␣-KG dehydrogenase, can be measured by 13 C NMR (27,40). Sequential 13 C NMR spectra were collected from SHM and LVH hearts to follow the incorporation of the 13 C label from [2,4,6,8,10,12,14, C 8 ]palmitate into endogenous glutamate pools. A nonlinear least-square fit of our established kinetic models of cardiac metabolism to 13 C NMR data for glutamate gave V TCA and F1 (i.e., as part of the malate-aspartate shuttle).…”

“…Whether altering calcium homeostasis with SERCA overexpression affects energy substrate metabolism (carbohydrates versus fatty acids) in the failing heart is unknown. Interestingly, it has been reported that the expression of SERCA2 in nonfailing transgenic mice led to a shift in substrate selection from fats to glucose metabolism (2). The potential for this shift in the failing heart could be advantageous (10,11).…”

Integrins protect cardiomyocytes from ischemia/reperfusion injury

“…Adv-CMV-mito-pericam and its use have been described previously (22,23). Mitochondrial membrane potential was measured using a JC-1 assay.…”

“…At 30 and 60 minutes following onset of reoxygenation, fluorescence measurements were performed at room temperature as described above with a Nikon Diaphot epifluorescent microscope. Fluorescence emission was filtered at 485 and 580 nm and directed to a photomultiplier tube (23).…”

“…We next measured mitochondrial [Ca 2+ ] using mitochondrial pericam (22,23). During normoxia there were no significant differences among groups ( Figure 5D).…”