Hyperpolarized 13C NMR observation of lactate kinetics in skeletal muscle

Abstract

The production of glycolytic end products, such as lactate, usually evokes a cellular shift from aerobic to anaerobic ATP generation and O 2 insufficiency. In the classical view, muscle lactate must be exported to the liver for clearance. However, lactate also forms under well-oxygenated conditions, and this has led investigators to postulate lactate shuttling from non-oxidative to oxidative muscle fiber, where it can serve as a precursor. Indeed, the intracellular lactate shuttle and the glycogen shunt hypotheses expand the vision to include a dynamic mobilization and utilization of lactate during a muscle contraction cycle. Testing the tenability of these provocative ideas during a rapid contraction cycle has posed a technical challenge. The present study reports the use of hyperpolarized [1- 13 C]lactate increases sharply and acetyl-L-carnitine, acetoacetate and glutamate levels also rise. Such a quick mobilization of pyruvate and lactate toward oxidative metabolism supports the postulated role of lactate in the glycogen shunt and the intracellular lactate shuttle models. The study thus introduces an innovative DNP approach to measure metabolite transients, which will help delineate the cellular and physiological role of lactate and glycolytic end products.

Comparative NMR and NIRS analysis of oxygen-dependent metabolism in exercising finger flexor muscles

“…However, both the intracellular lactate shuttle and glycogen shunt models require muscle to mobilize rapidly lactate into the acetyl CoA pool. Indeed, recent dynamic nuclear polarization (DNP) studies confirm that muscle can mobilize lactate rapidly and that pyruvate dehydrogenase can compete with lactate dehydrogenase to divert lactate into the acetyl CoA pool (75). The DNP experimental observations support a critical tenability of the glycogen shunt, lactate shuttle, and lactate as an energy buffer hypotheses.…”

“…Based on the Mb kinetics, the intracellular V O 2 shows no sign of delay. In fact, in recent 13 C dynamic nuclear polarization experiments, the relative PDH␣ (as reflected in the flux from Lac¡HCO 3 vs. Lac¡Pyr) shows that DCA can trigger an immediate rise in PDH␣, 37 times above the control level (75). PDH does not have any limitation in switching rapidly to its activated form to enhance acetyl CoA formation.…”

Voxel-by-voxel correlations of perfusion, substrate, and metabolite signals in dynamic hyperpolarized13C imaging

“…With [1‐ 13 C]lactate as the substrate, normalization of metabolite signals by the pyruvate signal compensates for polarization, injected dose, and substrate delivery to the tissue, because alanine and bicarbonate can be produced only after the tissue has converted the substrate to pyruvate. In addition to analyzing pairwise ratios of lactate, pyruvate, alanine, and bicarbonate signals, a recent HP 13 C NMR study of lactate kinetics in skeletal muscle, using [1‐ 13 C]lactate and [2‐ 13 C]pyruvate as substrates, considered ratios of lactate, pyruvate, alanine, and bicarbonate signals normalized by the total 13 C signal . Dynamic imaging data (Figure f) suggest that some perfusion information may be inferred from the (pyruvate + lactate) signal distribution when [1‐ 13 C]pyruvate is given as the substrate, which supports the use of total 13 C signal for normalization of metabolite signals to compensate for substrate perfusion on a voxel‐by‐voxel basis in 13 C imaging applications of skeletal muscle.…”

Multiorgan, Multimodality Imaging in Cardiometabolic Disease

“…Recent work has demonstrated the feasibility of in vivo investigations of skeletal muscle lactate and pyruvate kinetics. However, further work is required to translate these techniques into humans 13 .…”