Abstract

The number of identified human degenerative diseases with involvement of mitochondrial malfunction is steadily increasing. Therefore, the need for a detailed understanding of the physiologic controls of mitochondrial function in the living cell has become urgent. The experiments and analyses proposed in this application aim to develop a quantitative and integrated understanding of mitochondrial performance in the living cell, with emphasis on the sensitivity to cytosolic (ADP), to metabolic state influenced by the type of substrate, and to altered cytosolic (Ca++). Non-invasive spectroscopic and oxygen polarographic measurements of mitochondrial function will be made in excised mouse EDL (fast-twitch) and SOL (slow-twitch) muscles at rest and during contractile activity. The mitochondrial (ADP) response functions will be determined under control and physiologically and pharmacologically altered conditions. Completion of the stated aims will establish a paradigm for approaching similar quantitative questions in other cells and tissues. Further, the energy balance algorithm developed will provide a general predictive and analytical tool in the study of cell energetics and the relation to normal cell function and disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR036281-15
Application #
6044773
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Program Officer
Lymn, Richard W
Project Start
1988-10-01
Project End
2005-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
15
Fiscal Year
2000
Total Cost
$429,473
Indirect Cost

  Institution

Name
University of Washington
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Vinnakota, Kalyan C; Rusk, Joshua; Palmer, Lauren et al. (2010) Common phenotype of resting mouse extensor digitorum longus and soleus muscles: equal ATPase and glycolytic flux during transient anoxia. J Physiol 588:1961-83
Amara, Catherine E; Marcinek, David J; Shankland, Eric G et al. (2008) Mitochondrial function in vivo: spectroscopy provides window on cellular energetics. Methods 46:312-8
Arakaki, Lorilee S L; Burns, David H; Kushmerick, Martin J (2007) Accurate myoglobin oxygen saturation by optical spectroscopy measured in blood-perfused rat muscle. Appl Spectrosc 61:978-85
Conley, Kevin E; Jubrias, Sharon A; Amara, Catherine E et al. (2007) Mitochondrial dysfunction: impact on exercise performance and cellular aging. Exerc Sport Sci Rev 35:43-9
Conley, Kevin E; Amara, Catherine E; Jubrias, Sharon A et al. (2007) Mitochondrial function, fibre types and ageing: new insights from human muscle in vivo. Exp Physiol 92:333-9
Amara, Catherine E; Shankland, Eric G; Jubrias, Sharon A et al. (2007) Mild mitochondrial uncoupling impacts cellular aging in human muscles in vivo. Proc Natl Acad Sci U S A 104:1057-62
Vinnakota, Kalyan; Kemp, Melissa L; Kushmerick, Martin J (2006) Dynamics of muscle glycogenolysis modeled with pH time course computation and pH-dependent reaction equilibria and enzyme kinetics. Biophys J 91:1264-87
Dash, Ranjan K; Bell, Bradley M; Kushmerick, Martin J et al. (2005) Estimating in vitro mitochondrial oxygen consumption during muscle contraction and recovery: a novel approach that accounts for diffusion. Ann Biomed Eng 33:343-55
Kushmerick, Martin J (2005) From crossbridges to metabolism: system biology for energetics. Adv Exp Med Biol 565:171-80; discussion 180-2, 379-9
Marcinek, David J; Schenkman, Kenneth A; Ciesielski, Wayne A et al. (2005) Reduced mitochondrial coupling in vivo alters cellular energetics in aged mouse skeletal muscle. J Physiol 569:467-73

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