Conditions (such as aging) or diseases (such as diabetes and cystic fibrosis) can cause chronic changes in oxygen transport and cellular metabolism. A computational model of skeletal muscle energy metabolism during exercise and hypoxia can be use to investigate the regulation of oxygen utilization and cellular metabolism in skeletal muscle. This model will include detailed cellular pathways of glycolysis, fatty acid oxidation, oxidative phosphorylation, and the citric acid cycle. Model simulations can then be used to analyze and predict metabolic responses to increased work rate in trained and untrained animals, healthy young and old subjects, and patients with diabetes and cystic fibrosis. Non-invasive measurements of pulmonary oxygen uptake can be used as diagnostic and/or treatment tools for conditions such as aging and diseases such as diabetes and cystic fibrosis. However, the dynamics of pulmonary oxygen uptake at the mouth are two orders of magnitude slower than intracellular metabolic dynamics. Therefore, a multi-level mathematical model is required to integrate cellular respiration with whole-body responses. Animal experiments will be used to explore the role of non-oxidative pathways. On the cellular level, the specific aim at this point is to determine the role of reducing equivalents in feedforward mechanisms regulating oxygen consumption. Experiments in dogs (normal and with altered dehydrogenase activity) will be conducted at rest and during exercise to quantify the potential effects of reducing equivalent availability on citric acid cycle flux and oxidative phosphorylation in skeletal muscle mitochondria.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31GM084682-04
Application #
8303194
Study Section
Special Emphasis Panel (ZRG1-DIG-E (29))
Program Officer
Hagan, Ann A
Project Start
2009-02-01
Project End
2013-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$41,210
Indirect Cost
Name
Case Western Reserve University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Spires, Jessica; Gladden, L Bruce; Grassi, Bruno et al. (2013) Distinguishing the effects of convective and diffusive Oýýý delivery on VOýýý on-kinetics in skeletal muscle contracting at moderate intensity. Am J Physiol Regul Integr Comp Physiol 305:R512-21
Spires, Jessica; Lai, Nicola; Zhou, Haiying et al. (2011) Hemoglobin and myoglobin contributions to skeletal muscle oxygenation in response to exercise. Adv Exp Med Biol 701:347-52
Li, Yanjun; Solomon, Thomas P J; Haus, Jacob M et al. (2010) Computational model of cellular metabolic dynamics: effect of insulin on glucose disposal in human skeletal muscle. Am J Physiol Endocrinol Metab 298:E1198-209