Modular regulation analysis of integrative effects of hypoxia on the energetics of contracting skeletal muscle in vivo

Abstract

In the exercising muscle, acute reduction in ambient oxygen impairs muscle contraction because of the effects of hypoxia on mitochondrial ATP supply. The less marked impairment reported after long-term exposure to hypoxia points to changes in the regulation of the energetic system of contraction in HC (hypoxic conditioned) animals. This energetic system is conceptually defined here as two modules: the ATP/PCr (phosphocreatine)-producer and the ATP/PCr-consumer connected by energetic intermediates. Modular control analysis that combines top-down control analysis with non-invasive 31P-NMR spectroscopy was used to describe the effects of hypoxia on each module and their adaptation. Modulations of steady levels of ATP turnover (indirectly assessed as force output) and muscle PCr were obtained in HC rats (6 weeks at 10.5% O2) compared with N (normoxic) rats. Modular control and regulation analyses quantified the elasticity to PCr of each module in N and HC rats as well as the direct effect of acute hypoxia on the ATP/PCr-producer module. Similar elasticities in N and HC rats indicate the absence of response to long-term hypoxia in internal regulations of the ATP supply and demand pathways. The less marked impairment of contraction by acute hypoxia in HC rats (−9±6% versus −17±14% in N rats, P<0.05) was therefore fully explained by a lower direct effect (HC −31±13% versus N −44±23%, P<0.05) of acute hypoxia on mitochondrial ATP supply. This points to a positive adaptation to chronic hypoxia. Modular control analysis in vivo may provide powerful tools to find out improved function (alternatively dysfunction) at the system level in conditioned animals.