Classification and Mechanism of Fatigue Receptors

Budak, Cade
Previous studies both in animal and human models suggest that muscles are innervated by two different types of afferent neurons that selectively respond to concentrations of metabolites that build up following activity. One responds to relatively low metabolite concentrations and is therefore thought to act as a "fatigue" receptor that sends sensory feedback to autonomic centers to increase blood flow to muscle and promote clearance of metabolites. The second type only begins to responding when metabolite concentrations reach higher levels found when muscles experience energy depletion, ischemia and cramping, and is therefore thought to act as a "pain" receptor that helps promote muscle inactivity, relaxation and healing. What is unknown though, is the relative numbers of the two types of receptors and whether different muscles contain different densities of these receptors. Towards this end, we have used a novel mouse that enables us to visualize these neurons directly for the first time. These mice express the fluorescent protein GCaMP, a genetically encoded calcium indicator that "flashes" each time the neuron is activated by a stimulus. To provide appropriate stimuli, we injected varying concentrations of metabolites that were made up as a cocktail of different components (e.g., lactic acid, ATP, and protons) that have been found in the muscles of human subjects after varying degrees of exercise and thus mimic the conditions reported as mild, moderate, and severe fatigue, as well as pain. Having injected concentrations to the gastroc muscle of these mice at the femoral artery, we find with the low metabolite concentration one population of neurons responds to the stimulus. Then flushing out the first concentration and allowing receptors to clear and then injecting the higher metabolite concentration, a different population of neurons responds to the second stimulus. These results are preliminary but support the findings from earlier studies, the future studies will characterize these populations and their relative numbers further.
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