This application proposes a novel combination of magnetic resonance (MRS) and near infrared optical (NIRS) spectroscopy for studying energy metabolism in normal and abnormal human muscle. Our goal is to develop diagnostic procedures for human muscle function from principles of energy balances and their regulation developed by prior work on this grant. Metabolism, energetics and function of muscle are tightly integrated and provide crucial information needed to define normal and interpret abnormal muscle function in the intact human limb. In this application we add mouse muscle studies to test efficacy and accuracy of our quantitative spectroscopic methods. The first three specific aims exploit the notions of an integrative mass and energy balance developed in prior years of this grant to quantify the role of oxygen flux in the control of oxidative and glycolytic energy metabolism. First, we ask how mitochondria link O2 with ATP fluxes in oxidative phosphorylation (Aim 1). We evaluate the coupling between phosphorylation and oxidation with experiments that focus on cellular respiration in intact human muscle as a function of oxygen tension. These experiments are likely to establish new views of oxygen supply to mitochondria and the role of intracellular partial pressure of oxygen in the regulation of oxidative phosphorylation by [ADP]. Second, we examine how muscle diffusion conductance links O2 delivery with mitochondrial demand (Aim 2).
This aim compares the magnitude of the oxygen pressure gradient versus the diffusive conductance in oxygen uptake flux. Third, we evaluate how much the diffusion conductance for oxygen uptake influences the balance between glycolytic flux and H+ & lactate efflux (Aim 3). If our hypothesis is supported, diffusive conductance will be found to play a similar functional role for H+ & lactate balances and for oxygen balance. Finally, Aim 4 shows how this integration uniquely accounts for abnormal muscle energetics in aging. Thus this project links all the major components of energy balance governing the supply of ATP to the demands of cellular ATPases into a coherent whole and tests how alteration of these linkages and their regulation influences function, using elderly muscle as an example.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR041928-12
Application #
6699662
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Nuckolls, Glen H
Project Start
1993-02-01
Project End
2008-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
12
Fiscal Year
2004
Total Cost
$550,413
Indirect Cost
Name
University of Washington
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Conley, Kevin E (2016) Mitochondria to motion: optimizing oxidative phosphorylation to improve exercise performance. J Exp Biol 219:243-9
Ortega, Justus O; Lindstedt, Stan L; Nelson, Frank E et al. (2015) Muscle force, work and cost: a novel technique to revisit the Fenn effect. J Exp Biol 218:2075-82
Padowski, Jeannie M; Weaver, Kurt E; Richards, Todd L et al. (2014) Neurochemical correlates of caudate atrophy in Huntington's disease. Mov Disord 29:327-35
Feng, Shu; Chen, Daniel; Kushmerick, Martin et al. (2014) Multiparameter MRI analysis of the time course of induced muscle damage and regeneration. J Magn Reson Imaging 40:779-88
Lee, Donghoon; Marro, Kenneth; Mathis, Mark et al. (2014) In vivo absolute quantification for mouse muscle metabolites using an inductively coupled synthetic signal injection method and newly developed (1) H/(31) P dual tuned probe. J Magn Reson Imaging 39:1039-46
Marcinek, D J; Conley, K E (2014) In vivo metabolic spectroscopy identifies deficits in mitochondrial quality and capacity in aging skeletal muscle. Clin Pharmacol Ther 96:669-71
Conley, Kevin E; Jubrias, Sharon A; Cress, M Elaine et al. (2013) Exercise efficiency is reduced by mitochondrial uncoupling in the elderly. Exp Physiol 98:768-77
Conley, Kevin E; Jubrias, Sharon A; Cress, M Elaine et al. (2013) Elevated energy coupling and aerobic capacity improves exercise performance in endurance-trained elderly subjects. Exp Physiol 98:899-907
Coen, Paul M; Jubrias, Sharon A; Distefano, Giovanna et al. (2013) Skeletal muscle mitochondrial energetics are associated with maximal aerobic capacity and walking speed in older adults. J Gerontol A Biol Sci Med Sci 68:447-55
Conley, Kevin E; Amara, Catherine E; Bajpeyi, Sudip et al. (2013) Higher mitochondrial respiration and uncoupling with reduced electron transport chain content in vivo in muscle of sedentary versus active subjects. J Clin Endocrinol Metab 98:129-36

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