KINETICS OF MUSCLE METABOLISM BY POSITRON TRACERS

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Positron emission tomography (PET) of regional blood flow and metabolism in heart, brain and neoplastic tissue has introduced a new class of tracers to record cellular events in intact, functioning organs without destruction of the tissue. At the present time, further development of the PET technique is hampered by its semi-quantitative nature. The broad objective of this project is to exploit the unique characteristics of positron emitting isotopes for the quantitative study of muscle metabolism and for the correlation between metabolism and function in vivo. Prior experiments have demonstrated the utility of the glucose analog [18F]-2-deoxy-2-fluoro-D-glucose (FDG) for the rapid kinetic analysis of glucose uptake by heart and skeletal muscle as it relates to organ function, but the technique requires further validation. Radioactivity in the tissue is measured together with the FDG input function on a second-by-second basis. This technique not only provides reliable data for kinetic modeling, but also a means to test the hypothesis that there is a feedback system to match work and substrate C3 utilization on a beat-to-beat time scale. The isolated working rat heart will be used to correlate the kinetics of tracer uptake with direct measurements of the rate of glucose utilization under control conditions and after specific perturbations including competing substrates, stimulation of glucose transport by insulin, and ischemia/reperfusion. In vivo application of the technique to skeletal muscle will utilize the rabbit hindlimb under control conditions and during euglycemic/hyperinsulinemic clamps or during periods of increased contractile activity. For both hearts and skeletal muscle, differences in the kinetics of the analog and glucose in terms of intracellular phosphorylation and dephosphorylation will be assessed by direct biochemical measurements of the Km and Vmax of hexokinase and glucose 6-phosphatase for glucose and FDG. These analyses seek direct evidence for changes in key components of the correction factor relating tracer to tracee (lumped constant). Measurements of enzyme activities and intracellular metabolite levels will be used to assess the validity of the kinetic analyses. It is expected that we will obtain quantitative data on glucose metabolism in vivo which, in turn, provide critical information on the action of insulin in muscle as well as substrate metabolism and parameters of tissue viability on reperfusion of ischemic myocardium.