A deleterious systemic effect of chronic obstructive pulmonary disease (COPD) is peripheral muscle dysfunction, a condition that contributes to the exercise intolerance and reduced quality of life of COPD patients. The causes of the peripheral muscle dysfunction have yet to be fully elucidated. It has recently become clear that the hypoxia of COPD, oxidative stress within active muscle, and circulating inflammatory cytokines (particularly TNF-a) are potential mechanisms that may play a role in the muscle myopathy found in many COPD patients. However, there remains a paucity of data at the cellular level concerning the manner in which O2 availability to contracting skeletal muscle affects the interactions between intracellular PO2 (PjO2) and cell homeostasis, metabolic state, reactive O2 species (ROS) generation, and contractile function. We now use an isolated, intact single skeletal muscle fiber model in which slow- or fast-twitch fibers can be isolated from mice. By utilizing this model, intrinsic properties of contracting isolated single myofibers can be investigated without confounding factors related to the microcirculation, fiber recruitment patterns, and fiber type heterogeneities seen in whole muscle. We are proposing to use single isolated myofibers, from both healthy control mice and a model of pulmonary inflammation, to elucidate the regulatory pathways that are affected by P|O2 and thereby alter cellular function. Specifically, we are proposing to conduct experiments related to the general hypothesis that several important cellular regulatory factors (i.e. pH, Ca2+ handling, PI, fuel preference, ROS generation, etc.) are modualted by P|O2 (even at levels that do not inhibit oxidative phophorylation) which thereby modifies contractile function of the muscle fiber in a manner that is fiber type dependent. Our experimental preparation will allow us to precisely control the extracellular milieu, metabolic and respiratory rate will be varied by electrical stimulation, intracellular PO2 measured, specific pharmacological blockades will be induced, and intracellular fluorescent imaging (pH, Ca2+, ROS, PI, etc) will be conducted. The originality and significance of the proposed experiments will be to investigate the O2 dependence of regulatory pathways that determine oxidative stress and single myofiber function, which has important implications related to health at the cellular, organ, and whole body level, particularly during hypoxia or disease states involving hypoxia such as COPD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
La Jolla
United States
Zip Code
Park, Song-Young; Gifford, Jayson R; Andtbacka, Robert H I et al. (2014) Cardiac, skeletal, and smooth muscle mitochondrial respiration: are all mitochondria created equal? Am J Physiol Heart Circ Physiol 307:H346-52
Gifford, Jayson R; Ives, Stephen J; Park, Song-Young et al. (2014) ?1- and ?2-adrenergic responsiveness in human skeletal muscle feed arteries: the role of TRPV ion channels in heat-induced sympatholysis. Am J Physiol Heart Circ Physiol 307:H1288-97
Garten, Ryan S; Groot, H Jonathan; Rossman, Matthew J et al. (2014) The role of muscle mass in exercise-induced hyperemia. J Appl Physiol (1985) 116:1204-9
Zuo, Li; Hallman, Allison H; Roberts, William J et al. (2014) Superoxide release from contracting skeletal muscle in pulmonary TNF-? overexpression mice. Am J Physiol Regul Integr Comp Physiol 306:R75-81
Layec, Gwenael; Trinity, Joel D; Hart, Corey R et al. (2014) In vivo evidence of an age-related increase in ATP cost of contraction in the plantar flexor muscles. Clin Sci (Lond) 126:581-92
Trinity, Joel D; Groot, H Jonathan; Layec, Gwenael et al. (2014) Impact of age and body position on the contribution of nitric oxide to femoral artery shear rate: implications for atherosclerosis. Hypertension 63:1019-25
Donato, Anthony J; Henson, Grant D; Hart, Corey R et al. (2014) The impact of ageing on adipose structure, function and vasculature in the B6D2F1 mouse: evidence of significant multisystem dysfunction. J Physiol 592:4083-96
Ives, Stephen J; Harris, Ryan A; Witman, Melissa A H et al. (2014) Vascular dysfunction and chronic obstructive pulmonary disease: the role of redox balance. Hypertension 63:459-67
Cano, Isaac; Selivanov, Vitaly; Gomez-Cabrero, David et al. (2014) Oxygen pathway modeling estimates high reactive oxygen species production above the highest permanent human habitation. PLoS One 9:e111068
Wang, Eivind; Naess, Morten Svendsen; Hoff, Jan et al. (2014) Exercise-training-induced changes in metabolic capacity with age: the role of central cardiovascular plasticity. Age (Dordr) 36:665-76

Showing the most recent 10 out of 36 publications