Comparison of in vivo post-exercise PCr recovery and basal ATP synthesis flux for the assessment of skeletal muscle mitochondrial function

Introduction. It has been suggested that an impairment in skeletal muscle mitochondrial function plays a causative role in the development of insulin resistance and type 2 diabetes [1]. This hypothesis is predominantly based on in vitro measurements of for example gene expression and in vivo measurements of basal ATP synthesis flux with P MR saturation transfer (ST) experiments. However, the interpretation of P saturation transfer data is not straightforward. The lower basal ATP synthesis rates in insulin-resistant states [1, 2] could actually reflect a normal regulatory response to a lower energy demand, caused by impaired insulin signalling, rather than an impairment of intrinsic mitochondrial function [3-5]. Moreover, the Pi ATP fluxes obtained from P saturation transfer measurements are comprised of both ATP synthase flux and glycolytic exchange flux, with the latter contributing by as much as 80% [6, 7]. Therefore, decreased basal ATP synthesis rates do not necessarily reflect a mitochondrial defect. From dynamic P MRS measurements after exercise one can determine the phosphocreatine (PCr) recovery rate constant, which reflects in vivo muscle mitochondrial oxidative capacity because during recovery from exercise PCr is resynthesized purely as a consequence of oxidative ATP synthesis. Therefore, the post-exercise PCr recovery rate constant might be a better measure for in vivo mitochondrial function as compared to the basal ATP synthesis flux. In this study, both post-exercise PCr recovery and basal ATP synthesis flux were measured in a rat model of mitochondrial dysfunction and compared with oxygen consumption in isolated mitochondria.