Analysis Of Oxygen Diffusion Limitation In Contracting Skeletal Muscle During Higher ATP Demand

Abstract

PURPOSE: The relationship of intracellular O2 (iPO2) to skeletal muscle work rate (WR) appears to be different between two human studies. One study found that iPO2 reached a plateau at 60% of maximal work rate, while another study found iPO2 decreased linearly with work rate. These apparently contradictory results suggest alternative mechanisms with respect to O2 diffusion rate from capillary blood to myocytes. To quantitatively analyze the experimental data, a mechanistic, computational model was used to simulate muscle oxygen uptake (VO2m) in response to muscle contraction. With this model, iPO2 changes with increased energy demand (ATP flux) can be simulated under different experimental conditions. METHODS: A mechanistic, mathematical model was developed to simulate O2 transport and cellular metabolism in skeletal muscle. This model accounts for anaerobic glycolysis, which plays an important role in ATP homeostasis at higher intensity exercise. The model simulated experimental VO2m dynamics of canine muscle electrically stimulated in situ under various conditions (O2 content, blood flow, stimulus intensity) that mimic human exercise at different WR. The effect of O2 diffusion limitation at higher rates of muscle contraction was examined by simulating the oxygen gradient (ΔPO2) between capillary blood and tissue cells and glycolytic flux as well as iPO2 for different values of permeability-surface area (PS). RESULTS: Simulated responses were obtained with skeletal muscle contraction at constant (perfused) blood flow under normoxia for different PS values. With a high PS (200mL/mL-min), simulations show that as relative work rate (%WRmax) increases, both ΔPO2 and glycolytic flux increase, while iPO2 decreases and ATP concentration [ATP] remains constant. From 80% to 100% WRmax, however, [ATP] decreases from 6.5 to 6 mM and iPO2 decreases from 24 to 12 mmHg. With a low PS (80mL·mL−1·min−1), a WR increase leads to an increase of both ΔPO2 and glycolytic flux and an iPO2 decrease. Above 75% WRmax, however, the increase of ΔPO2 and decrease of iPO2 is much less and tends to plateau. At 100% WRmax, ΔPO2=40 mmHg, iPO2=3mmHg, and [ATP] =4.5mM. CONCLUSION: These model simulations demonstrate that the relationship of iPO2 to work rate depends on the experimental conditions and can account for apparently conflicting experimental observations. This analysis suggests that the VO2m response to high intensity exercise is limited by O2 diffusion. Supported by NIH-NIDDK, GM088823-01 and NSF 0743705.