Regulation of free radical outflow from an isolated muscle bed in exercising humans.
ABSTRACT Incremental knee extensor (KE) exercise performed at 25, 70, and 100% of single-leg maximal work rate (WR(MAX)) was combined with ex vivo electron paramagnetic resonance (EPR) spectroscopic detection of alpha-phenyl-tert-butylnitrone (PBN) adducts, lipid hydroperoxides (LH), and associated parameters in five males. Blood samples were taken from the femoral arterial and venous circulation that, when combined with measured changes in femoral venous blood flow, permitted a direct examination of oxidant exchange across a functionally isolated contracting muscle bed. KE exercise progressively increased the net outflow of LH and PBN adducts (100% > 70% > 25% WR(MAX), P < 0.05) consistent with the generation of secondary, lipid-derived oxygen (O(2))-centered alkoxyl and carbon-centered alkyl radicals. Radical outflow appeared to be more intimately associated with predicted decreases in intracellular Po(2) (iPo(2)) as opposed to measured increases in leg O(2) uptake, with greater outflow recorded between 25 and 70% WR(MAX) (P < 0.05 vs. 70-100% WR(MAX)). This bias was confirmed when radical venoarterial concentration differences were expressed relative to changes in the convective components of O(2) extraction and flow (25-70% WR(MAX) P < 0.05 vs. 70-100% WR(MAX), P > 0.05). Exercise also resulted in a net outflow of other potentially related redox-reactive parameters, including hydrogen ions, norepinephrine, myoglobin, lactate dehydrogenase, and uric acid, whereas exchange of lipid/lipoproteins, ascorbic acid, and selected lipid-soluble anti-oxidants was unremarkable. These findings provide direct evidence for an exercise intensity-dependent increase in free radical outflow across an active muscle bed that was associated with an increase in sarcolemmal membrane permeability. In addition to increased mitochondrial electron flux subsequent to an increase in O(2) extraction and flow, exercise-induced free radical generation may also be regulated by changes in iPo(2), hydrogen ion generation, norepinephrine autoxidation, peroxidation of damaged tissue, and xanthine oxidase activation.
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ABSTRACT: Today, many different tools are developed to execute and visualize physiological models that represent the human physiology. Most of these tools run models written in very specific programming languages which in turn simplify the communication among models. Nevertheless, not all of these tools are able to run models written in different programming languages. In addition, interoperability between such models remains an unresolved issue. In this paper we present a simulation environment that allows, first, the execution of models developed in different programming languages and second the communication of parameters to interconnect these models. This simulation environment, developed within the Synergy-COPD project, aims at helping and supporting bio-researchers and medical students understand the internal mechanisms of the human body through the use of physiological models. This tool is composed of a graphical visualization environment, which is a web interface through which the user can interact with the models, and a simulation workflow management system composed of a control module and a data warehouse manager. The control module monitors the correct functioning of the whole system. The data warehouse manager is responsible for managing the stored information and supporting its flow among the different modules. It has been proved that the simulation environment presented here allows the user to research and study the internal mechanisms of the human physiology by the use of models via a graphical visualization environment. A new tool for bio-researchers is ready for deployment in various use cases scenarios.Journal of Translational Medicine 11/2014; 12 Suppl 2:S7. · 3.99 Impact Factor
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ABSTRACT: We investigated the relationship between markers of mitochondrial biogenesis, cell signaling, and antioxidant enzymes by depleting skeletal muscle glutathione with diethyl maleate (DEM) which resulted in a demonstrable increase in oxidative stress during exercise. Animals were divided into six groups: (1) sedentary control rats; (2) sedentary rats + DEM; (3) exercise control rats euthanized immediately after exercise; (4) exercise rats + DEM; (5) exercise control rats euthanized 4 h after exercise; and (6) exercise rats + DEM euthanized 4 h after exercise. Exercising animals ran on the treadmill at a 10% gradient at 20 m/min for the first 30 min. The speed was then increased every 10 min by 1.6 m/min until exhaustion. There was a reduction in total glutathione in the skeletal muscle of DEM treated animals compared to the control animals (P < 0.05). Within the control group, total glutathione was higher in the sedentary group compared to after exercise (P < 0.05). DEM treatment also significantly increased oxidative stress, as measured by increased plasma F2-isoprostanes (P < 0.05). Exercising animals given DEM showed a significantly greater increase in peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α) mRNA compared to the control animals that were exercised (P < 0.05). This study provides novel evidence that by lowering the endogenous antioxidant glutathione in skeletal muscle and inducing oxidative stress through exercise, PGC-1α gene expression was augmented. These findings further highlight the important role of exercise induced oxidative stress in the regulation of mitochondrial biogenesis. © 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.Physiological reports. 12/2014; 2(12).
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ABSTRACT: The production of reactive oxygen species (ROS) from the inner mitochondrial membrane is one of many fundamental processes governing the balance between health and disease. It is well known that ROS are necessary signaling molecules in gene expression, yet when expressed at high levels, ROS may cause oxidative stress and cell damage. Both hypoxia and hyperoxia may alter ROS production by changing mitochondrial Po2 ([Formula: see text]). Because [Formula: see text] depends on the balance between O2 transport and utilization, we formulated an integrative mathematical model of O2 transport and utilization in skeletal muscle to predict conditions to cause abnormally high ROS generation. Simulations using data from healthy subjects during maximal exercise at sea level reveal little mitochondrial ROS production. However, altitude triggers high mitochondrial ROS production in muscle regions with high metabolic capacity but limited O2 delivery. This altitude roughly coincides with the highest location of permanent human habitation. Above 25,000 ft., more than 90% of exercising muscle is predicted to produce abnormally high levels of ROS, corresponding to the "death zone" in mountaineering.PLoS ONE 11/2014; 9(11):e111068. · 3.53 Impact Factor