Catabolic activity in muscles is regulated with the amount of exercise a muscle performs, and muscle contractions are controlled by motor neurons. However, there could be a more direct link between the nervous system and muscle metabolism, as Tim Mentel and colleagues report in their recent J. Neurosci. paper. They have found that one of the cell signaling pathways that activates glycolysis metabolism during locust flight is under control of a set of identified modulatory neurons.
Migratory locusts are extremely determined flyers. Their flight muscles are fueled by carbohydrates during take-off and for short distances, but they switch to lipid metabolism for longer flights. Two key players regulate glycolysis in these muscles: octopamine, which is a neuromodulator and neurohormone in insects, and fructose 2,6-bisphosphate (F2,6P2), which is a potent activator of glycolysis control enzymes. F2,6P2 levels decrease during prolonged flight sequences and thus glycolysis is downregulated when the muscles switch to fat metabolism. Octopamine levels in the muscle also decrease during flight, and increasing octopamine levels experimentally keeps F2,6P2 levels and glycolysis up.
But what regulates octopamine levels in these muscles? It could be supplied by the blood system, but hemolymph levels of octopamine rise during longer flights, so the source is unlikely to be hormonal. Instead, the authors suspected that muscular octopamine could be supplied by nerve cells as they knew that the thoracic central nervous system of insects contains neurons that release octopamine directly onto skeletal muscles. Some of the so-called dorsal unpaired median (DUM) neurons innervate flight muscles and, consistent with a putative role in regulating octopamine levels in flight muscles, this subset is active at rest and inhibited during flight.
First they tested whether the activity of DUM neurons could increase F2,6P2 levels. They stimulated the DUM neurons at frequencies in the range observed in the resting animal, and consistently elevated the level of F2,6P2 in the muscle. Therefore, DUM neuron activity would be sufficient to keep F2,6P2 levels high in the resting animal, which would keep the flight muscles poised for the high carbohydrate oxidation rates used for take-off.
But how does octopamine released from the nerve trigger an increase in the levels of F2,6P2 in the flight muscle? Octopamine receptors act through second messenger cascades, and Mentel and colleagues wanted to find the signaling molecules that link the neuromodulator to the metabolic enzymes. In another set of experiments they showed that DUM neuron activity affected F2,6P2 levels partly through the cAMP/protein kinase A (PKA) pathway. Stimulating DUM neurons was sufficient to increase PKA levels in the muscles, and a PKA inhibitor blocked the increase of F2,6P2 in response to DUM neuron stimulation. However, just increasing PKA levels in the muscles pharmacologically had no effect, indicating that a parallel pathway must also be involved.
This is the first case showing a neuromodulator's direct action on muscle metabolism. Modulatory neurons release substances into many different tissues, including the blood and the nervous system itself, so one might speculate that in many systems neuromodulators may provide a link between changing behavioral states and adjustment to changing catabolic demands.
- © The Company of Biologists Limited 2003