Brain and Muscle Energy Group & Electron Microscopy Laboratory,

Department of Oral Biology      

 

 

Linda Hildegard Bergersen, PhD  

Professor of Physiology, and

Dean of Research, Faculty of Dentistry, University of Oslo, Norway

Professor of Neurobiology of Aging, University of Copenhagen, Denmark


Affiliation details:

  Professor of Physiology

Department of Oral Biology (DOB)

 

  Group Leader  

Brain and Muscle Energy Group & Electron Microscopy Laboratory 

Department of Oral Biology 

 

  Dean of Research and Researcher Training

Faculty of Dentistry, Office of the Dean  

University of Oslo, Norway 

 

  Professor in Neurobiology of Aging 
Center for Healthy Aging (
CEHA) &
Department of Neuroscience and Pharmacology (
INF)
Panum Institute, Building 18.1

University of Copenhagen, Denmark

 

Post: PO Box 1052 Blindern, 0316 Oslo, Norway

Visit: Domus Odontologica, Room A1.M082, Sognsvannsveien 9, 0372 Oslo, Norway

Mobile telephone: +47 97032049

Email: l.h.bergersen@odont.uio.no   

 

 

 

17 Linda_Bergersen Compr

Photo:  Elmer Laahne, for Nasjonalt medisinsk museum/Norsk teknisk museum

 

I have pursued research on physical exercise-generated lactate since my days as MSc student. I obtained my PhD in 2001 based on work done at the University of Oslo. After a postdoc period 2002-2004, in Oslo and in Lausanne, on a personal grant from the Research Council of Norway, I established my research groups, in Oslo and in Copenhagen. I was leader of the SN-Lab of the Centre for Molecular Biology and Neuroscience (CMBN) and Institute of Basic Medical Sciences, University of Oslo 2009-2012.

My current joint positions at the Center for Healthy Aging (CEHA), University of Copenhagen (2011-), and at the Department of Oral Biology, University of Oslo (2012-), with affiliation at Molecular Medicine, University of Oslo, and an extensive national and international collaborative network, provide optimized gain from my combined expertise in molecular biology and neuroscience, particularly for healthy brain ageing and dementia research.

 

 

 

 

‘Breaking News’:  Why is physical exercise good for the brain?

In numerous investigations, physical exercise is the most effective measure against dementia, and is beneficial against normal aging and several brain diseases; how does information from muscles reach the brain? We just found out:

Active muscles deliver large quantities of lactate to the blood and thereby to the brain, where it hits a receptor protein, the lactate receptor HCAR1. The activated HCAR1 causes production of growth factors, such as VEGF, which stimulates nerve cells and causes formation of new capillaries – the thinnest blood vessels, where the vital substance exchange takes place. Seven weeks of high intensity interval training five days a week, or injections of lactate to reach similar blood lactate levels, caused increase of VEGF and capillaries in hippocampus in wild-type mice, but not in knockout mice lacking HCAR1.

This is the first time that a substance from exercising muscle has been shown to change the brain through an identified receptor. As impaired blood supply and nerve cell death are key problems in aging and neurodegenerative diseases, including Alzheimer’s disease, the findings open a new approach to treatment.

Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1

Morland C, Andersson KA, Haugen ØP, Hadzic A, Kleppa L, Gille A, Rinholm JE, Palibrk V, Diget EH, Kennedy LH, Stølen T, Hennestad E, Moldestad O, Cai Y, Puchades M, Offermanns S, Vervaeke K, Bjørås M, Wisløff U, StormMathisen J, Bergersen LH.

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

 

 

 

 

Synopsis

As a triathlete, I had early personal experience with lactate. Ever since, I have tried to understand the intriguing actions of lactate in the body.

My early electron microscopic and light microscopic work pioneered and identified the localization of different types of lactate transporters (MCTs) that underlie the ability of lactate to be transported from cells and organs of high production to sites of high demand. For example, active glycolytic muscle fibres release large quantities of lactate to be used by oxidative fibres in skeletal muscle or by the heart and brain.

Subsequently we discovered that the brain has a lactate receptor (HCAR1, GPR81). This downregulates cellular cAMP levels and also has other down-stream effects. Recently we found that this receptor mediates (at least some of) the supportive effects of exercise on the brain (see Box ‘Breaking News’ and below).

The new discovery opens a new field of research with HCAR1 as a potential target for therapy and development of ‘neutraceuticals’, an ‘exercise pill’. While exercise should be encouraged because of its multiple benefits for the whole body, most people at risk of dementia are not able to attain an optimum level of exercise for stimulating the receptor. This may be overcome by an ‘exercise pill’.

 

 

Roles of the HCAR1 in brain

Under the Research Council of Noway sponsored Project number 214458 "How does physical exercise translate into better brains?" we discovered that the lactate receptor HCAR1 is expressed and active in brain (Lauritzen KH et al 2014 Cereb Cortex   Coverpicture) and now present the first demonstration of a physiological role of this receptor in the living brain (Morland C, Andersson KA et al 2017 Nat Commun): HCAR1 mediates an exercise induced increase in the neuro-vasculo-trophic growth factor VEGF and in capillary density in brain (Figure 1). The exercise effect was reproduced by injection of lactate to achieve similar blood lactate levels. The effects were abolished in knockout mice lacking HCAR1. The change in VEGF and capillary density comprised the dentate hilus of hippocampus known to undergo adult neurogenesis induced by exercise. In cerebellum the same wild-type mice showed no significant change in VEGF or capillary density.

 

The localization of HCAR1 was revealed in mRFP-HCAR1 reporter mice expressing monomeric red fluorescent protein under the HCAR1 promoter (Figure 2). It turned out to be very highly concentrated in pial cells adjacent to the blood vessels supplying the brain, in their course in the pia mater, and accompanying the vessels as they penetrate into the brain parenchyma, partly expressing pericyte markers such as platelet-derived growth factor receptor β (PDGFRβ). This means that HCAR1 is at a strategic site for monitoring entry and exit of lactate in brain, for influencing brain blood flow and drainage of brain extracellular fluid.

 

 

 

 

Figure 1 | Systemic lactate injections (lactate) and treadmill training (exercise) lead to HCAR1 dependent increase in the density of blood vessels and VEGF in the brain.

a & c, Confocal micrographs of blood vessels (collagen IV, green) in wild type mice (wt) and HCAR1 knockout mice (KO) subjected to lactate treatment and exercise, a, cerebral cortex. c, hippocampus.

b & d, Quantification of the effects of lactate and exercise on the density of blood vessels in wt and HCAR1 KO mice.

e & f, Quantification of the effects of lactate and exercise on the level of VEGF in hippocampus in wt and HCAR1 KO mice.

g, Western blot analysis of VEGF in the hippocampus of wt and HCAR1 KO mice exposed to the treatments described above. α-tubulin (α-tub) was used as a loading control.

 

(From Figure 1 of  Morland C, Andersson KA,,  Bergersen LH 2017 Nat Commun)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 2 | mRFP-HCAR1 (red) is highly expressed in meningeal-like / preicyte-like cells along blood vessels supplying the brain.

i, Vessel (basal membrane collagen IV, green) penetrating into the hippocampus through the extension of pia in the fissura hippocampi (indicated by white asterisks, brain surface to the left outside the picture), processes . HCAR1 cells wrap processes around vessel.

j-l, Small vessel in the cerebral neocortex, surrounded by cell co-expressing mRFP-HCAR1 (j, red; l, yellow) and the pericyte-associated protein PDGFRβ (k, green; l, yellow). Staining of nuclei (arrow and arrowhead, DAPI, white) reveals that an endothelial cell (arrowhead) is located between the lumen and the mRFP-HCAR1 / PDGFRβ-co-expressing cell.

(From Figure 3 of Morland C, Andersson KA,,  Bergersen LH 2017 Nat Commun)

 

 

 

Figure 3 | Organization of cells that carry HCAR1 and of the angiogenic action of lactate.

 

Blood-borne lactate from exercising muscle penetrates the blood vessel wall (yellow) through monocarboxylate transporters located in the vascular endothelium (ie, the blood–brain barrier). Extravascular lactate (from blood or generated in the brain parenchyma upon neural activation) is freely diffusible in the perivascular / subpial space, thereby bathing the leptomeningeal fibroblast-like cells carrying HCAR1 (red). Magnified inset indicates possible, yet unidentified (?), pathways leading from activation of HCAR1 in the cells in pia and perivascular sheaths to increased VEGFA and subsequent enhanced angiogenesis.

 

(Figure 5 of Morland C, Andersson KA,,  Bergersen LH 2017 Nat Commun)

 

 

 

 

 

 

 

From Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1 by Cecilie Morland, Krister A. Andersson, Øyvind P. Haugen, Alena Hadzic, Liv Kleppa, Andreas Gille, Johanne Egge Rinholm, Vuk Palibrk, Elisabeth Holm Diget, Lauritz H. Kennedy, Tomas Stølen, Eivind Hennestad, Olve Moldestad ,Yiqing Cai, Maja Puchades, Stefan Offermanns, Koen Vervaeke, Magnar Bjørås, Ulrik Wisløff, Jon Storm-Mathisen, and Linda H. Bergersen 2017

Nat Commun 23;8:15557 (accepted for publication 7th  April 2017, published online 23rd May 2017) doi: 10.1038/ncomms15557

 

 

 

 

General overview

The function of both brain and muscle depends crucially on their energy supply. The brain uses most of its energy on electrical signalling, along and between neurons. Brain energy supply is highly dependent on glucose, but can also be sustained by lactate, eg, entering from blood during physical exercise. Lactate is produced by the brain, such as in aerobic glycolysis, for fast ATP production and generation of anabolic products for protein and lipid synthesis, and acts as a signalling molecule transmitting signals about the energy state of active brain cells. The latter concept was substantiated by our discovery of the existence and action of the lactate receptor, HCAR1 (also known as HCA1 or GPR81), in the brain (Fig 1). Our main research focus is now on the hypothesis that HCAR1 mediates some of the dementia-protective and other ameliorative effects of physical exercise on diseases of the brain. Of particular interest is whether HCAR1 activation can delay or stop cognitive decline from mild cognitive impairment into dementia.

Brain neurons contact each other at synapses. A synapse consists of a presynaptic terminal and a postsynaptic dendrite, separated by a 20 nm wide synaptic cleft, into which the neurotransmitter (eg, glutamate and GABA) is released from presynaptic vesicle stores to activate receptor proteins at outward facing binding sites. Glial cells, primarily astrocytes, tightly surround the synapse, contributing to signalling as the third member of the ‘tripartite synapse’ (Fig 2). Information transmission at synapses is based on ion fluxes through the postsynaptic cell membrane. The ions that enter or leave the cell must later be pumped out or in again, consuming energy. Whereas glutamate and GABA exert their primary effects at the synapse, part of the released transmitter molecules escape the synaptic gap and diffuse to deliver their signal via extracellular receptors in a larger volume of brain tissue surrounding the active synapse. Lactate and many other molecules with signalling roles through receptors, are released and act predominantly outside synaptic sites.

 

 

 

 

Fig 1.  L-lactate transport and action at the ‘tripartite synapse’ of axon, dendrite, and astrocyte, and at the glio-vascular junction. Lactate, formed by glycolysis in brain cells or entering from blood, migrates down concentration gradients (of lactate and cotransported proton) between intracellular and extracellular compartments of neurons, astrocytes, and endothelial cells (orange circle), catalyzed by monocarboxylate transporters (MCT1, MCT2, and MCT4, red ovals). Lactate also migrates along the extracellular space, as well as throughout the astrocytic syncytial network via connexin gap junctions (Cx, orange oval). HCAR1 (red rectangles), lactate receptors. GLUT1 and GLUT3 (green ovals), glucose transporters. Positions of ionotropic glutamate receptors (AMPA-R, purple rectangles) and metabotropic glutamate receptors (blue serpents), influencing and influenced by lactate, are indicated. Mitochondria (dark-blue symbols) shun dendritic spines and thin astroglial processes. Astroglial processes contain glycogen particles (green spheres). From Bergersen LH (2015) Lactate transport and signaling in the brain: potential therapeutic targets and roles in body-brain interaction. J Cereb Blood Flow Metab 35(2):176-185