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 #
7R01HL072011-11
Application #
8728995
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Lee, Albert
Project Start
2002-12-01
Project End
2017-05-31
Budget Start
2014-08-01
Budget End
2015-05-31
Support Year
11
Fiscal Year
2014
Total Cost
$349,481
Indirect Cost
$88,337
Name
University of Michigan Ann Arbor
Department
Physiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Bakermans, Adrianus J; Abdurrachim, Desiree; van Nierop, Bastiaan J et al. (2015) In vivo mouse myocardial (31)P MRS using three-dimensional image-selected in vivo spectroscopy (3D ISIS): technical considerations and biochemical validations. NMR Biomed 28:1218-27
van Brussel, Marco; van Oorschot, Joep W M; Schmitz, Joep P J et al. (2015) Muscle Metabolic Responses During Dynamic In-Magnet Exercise Testing: A Pilot Study in Children with an Idiopathic Inflammatory Myopathy. Acad Radiol 22:1443-8

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