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Nat Commun. 2017 May 23;8:15557. doi: 10.1038/ncomms15557.

Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1.

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The Brain and Muscle Energy Group, Electron Microscopy Laboratory, Department of Oral Biology, University of Oslo, NO-0316 Oslo, Norway.
Institute for Behavioral Sciences, Faculty of Health Sciences, Oslo and Akershus University College, NO-0167 Oslo, Norway.
The Synaptic Neurochemistry Lab, Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, Healthy Brain Ageing Centre, University of Oslo, NO-0317 Oslo, Norway.
Institute for Experimental and Clinical Pharmacology and Toxicology, Mannheim Medical Faculty, Heidelberg University, D-68169 Mannheim, Germany.
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway.
Center for Healthy Aging, Department of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
K.G. Jebsen Center of Exercise in Medicine, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway.
Laboratory of Neural Computation, Department of Physiology, University of Oslo, NO-0317 Oslo, Norway.
Centre for Rare Disorders, Oslo University Hospital, Rikshospitalet, NO-0424 Oslo, Norway.
Max-Planck-Institute for Heart and Lung Research, Department of Pharmacology, D-61231 Bad Nauheim, Germany.


Physical exercise can improve brain function and delay neurodegeneration; however, the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 enhances cerebral vascular endothelial growth factor A (VEGFA) and cerebral angiogenesis. High-intensity interval exercise (5 days weekly for 7 weeks), as well as L-lactate subcutaneous injection that leads to an increase in blood lactate levels similar to exercise, increases brain VEGFA protein and capillary density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle shows no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. Thus, we demonstrate that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor.

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