ATP synthesis in the healthy mammalian heart is primarily oxidative, with greater than 95% of ATP synthesized in the mitochondria via oxidative phosphorylation. In the failing heart, ATP synthesis is compromised, with result that that chemical energy, in the form of the ATP hydrolysis potential, available for the heart to do work is diminished. This R01 research program, which was first funded in April 2004 and renewed in September 2008, has made substantial progress in both elucidating the physiological mechanisms underlying control of oxidative phosphorylation and in determining how these mechanisms break down in heart failure. Specifically, we have: (1.) disproved the previous accepted theory that oxidative phosphorylation and energetic state in the heart are maintained in the absence of a feedback mechanism;(2.) demonstrated how inorganic phosphate acts as the key feedback signal controlling the rate of mitochondrial ATP synthesis in the heart in vivo;and (3.) shown how the depletion of cytoplasmic metabolite pools in the myocardium affects energetic state in heart failure. The proposal for renewed funding focuses on more deeply characterizing our understanding of the oxidative metabolism in the heart, and translating our basic findings to human studies. We will expand and develop our computer models of myocardial energy metabolism by utilizing the substantial foundation of software and data resources that we have established. Models will be parameterized and validated based on kinetic time-course experiments using purified mitochondria obtained from male Dahl S and SS.BN13 rats maintained on low- and high-salt diets. (The high-salt Dahl S is an established hypertensive dilated myopathy model, where the SS.BN13 groups serve as controls.) In parallel human studies, we will obtain the first in vivo measurements of phosphate metabolites in human hearts over a range of work rates and the first measurements of energetic state in healthy and diseased subjects during exercise. These studies will determine if, and to what extent, the ability of ATP synthesis to keep up with increasing demand provides additional insight into clinical phenotypes. Finally, based on the findings from the rat models and human studies, we will use computer simulation to determine if and how changes in energy state can explain cardiac pumping failure in vivo.

Public Health Relevance

We propose to use experiments in animal models, measurements in human subjects, and computer simulation of the biochemical processes involved in cardiac energy metabolism to determine how the system is regulated and to probe changes that occur in heart failure. In addition to determining and validating the mechanisms that impair the ability of heart muscle to provide chemical energy for cellular function, we will determine if and how changes in energy state can explain cardiac pumping failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL072011-10A1
Application #
8577670
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Larkin, Jennie E
Project Start
2002-12-01
Project End
2017-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2013
Total Cost
$326,869
Indirect Cost
$68,810
Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Bazil, Jason N; Pannala, Venkat R; Dash, Ranjan K et al. (2014) Determining the origins of superoxide and hydrogen peroxide in the mammalian NADH:ubiquinone oxidoreductase. Free Radic Biol Med 77:121-9
Schmitz, J P J; Groenendaal, W; Wessels, B et al. (2013) Combined in vivo and in silico investigations of activation of glycolysis in contracting skeletal muscle. Am J Physiol Cell Physiol 304:C180-93
Li, Xin; Wu, Fan; Beard, Daniel A (2013) Identification of the kinetic mechanism of succinyl-CoA synthetase. Biosci Rep 33:145-63
Schmitz, Joep P J; Jeneson, Jeroen A L; van Oorschot, Joep W M et al. (2012) Prediction of muscle energy states at low metabolic rates requires feedback control of mitochondrial respiratory chain activity by inorganic phosphate. PLoS One 7:e34118
Li, Xin; Wu, Fan; Qi, Feng et al. (2011) A database of thermodynamic properties of the reactions of glycolysis, the tricarboxylic acid cycle, and the pentose phosphate pathway. Database (Oxford) 2011:bar005
Pradhan, Ranjan K; Qi, Feng; Beard, Daniel A et al. (2011) Characterization of Mg2+ inhibition of mitochondrial Ca2+ uptake by a mechanistic model of mitochondrial Ca2+ uniporter. Biophys J 101:2071-81
Qi, Feng; Pradhan, Ranjan K; Dash, Ranjan K et al. (2011) Detailed kinetics and regulation of mammalian 2-oxoglutarate dehydrogenase. BMC Biochem 12:53
Thompson, Matthew D; Beard, Daniel A (2011) Development of appropriate equations for physiologically based pharmacokinetic modeling of permeability-limited and flow-limited transport. J Pharmacokinet Pharmacodyn 38:405-21
Carlson, Brian E; Beard, Daniel A (2011) Mechanical control of cation channels in the myogenic response. Am J Physiol Heart Circ Physiol 301:H331-43
Beard, Daniel A (2011) Simulation of cellular biochemical system kinetics. Wiley Interdiscip Rev Syst Biol Med 3:136-46

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