Model of oxygen transport and metabolism predicts effect of hyperoxia on canine muscle oxygen uptake dynamics

Abstract

Previous studies have shown that increased oxygen delivery, via increased convection or arterial oxygen content, does not speed the dynamics of oxygen uptake, V̇o2m, in dog muscle electrically stimulated at a submaximal metabolic rate. However, the dynamics of transport and metabolic processes that occur within working muscle in situ is typically unavailable in this experimental setting. To investigate factors affecting V̇o2m dynamics at contraction onset, we combined dynamic experimental data across working muscle with a mechanistic model of oxygen transport and metabolism in muscle. The model is based on dynamic mass balances for O2, ATP, and PCr. Model equations account for changes in cellular ATPase, oxidative phosphorylation, and creatine kinase fluxes in skeletal muscle during exercise, and cellular respiration depends on [ADP] and [O2]. Model simulations were conducted at different levels of arterial oxygen content and blood flow to quantify the effects of convection and diffusion of oxygen on the regulation of cellular respiration during step transitions from rest to isometric contraction in dog gastrocnemius muscle. Simulations of arteriovenous O2 differences and V̇o2m dynamics were successfully compared with experimental data (Grassi B, Gladden LB, Samaja M, Stary CM, Hogan MC. J Appl Physiol 85: 1394–1403, 1998; and Grassi B, Gladden LB, Stary CM, Wagner PD, Hogan MC. J Appl Physiol 85: 1404–1412, 1998), thus demonstrating the validity of the model, as well as its predictive capability. The main findings of this study are: 1) the estimated dynamic response of oxygen utilization at contraction onset in muscle is faster than that of oxygen uptake; and 2) hyperoxia does not accelerate the dynamics of diffusion and consequently muscle oxygen uptake at contraction onset due to the hyperoxia-induced increase in oxygen stores. These in silico derived results cannot be obtained from experimental observations alone.