Article

Diabetologia

, Volume 52, Issue 7, pp 1409-1418

First online:

Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase

  • V. B. MatthewsAffiliated withCellular and Molecular Metabolism Laboratory, Diabetes and Metabolism Division, Baker Heart Research Institute
  • , M.-B. ÅströmAffiliated withThe Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC, Rigshospitalet—Section 7641, Faculty of Health Sciences, University of Copenhagen
  • , M. H. S. ChanAffiliated withCellular and Molecular Metabolism Laboratory, Diabetes and Metabolism Division, Baker Heart Research Institute
  • , C. R. BruceAffiliated withCellular and Molecular Metabolism Laboratory, Diabetes and Metabolism Division, Baker Heart Research Institute
  • , K. S. KrabbeAffiliated withThe Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC, Rigshospitalet—Section 7641, Faculty of Health Sciences, University of Copenhagen
  • , O. PrelovsekAffiliated withCellular and Molecular Metabolism Laboratory, Diabetes and Metabolism Division, Baker Heart Research Institute
  • , T. ÅkerströmAffiliated withThe Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC, Rigshospitalet—Section 7641, Faculty of Health Sciences, University of Copenhagen
  • , C. YfantiAffiliated withThe Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC, Rigshospitalet—Section 7641, Faculty of Health Sciences, University of Copenhagen
  • , C. BroholmAffiliated withThe Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC, Rigshospitalet—Section 7641, Faculty of Health Sciences, University of Copenhagen
    • , O. H. MortensenAffiliated withThe Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC, Rigshospitalet—Section 7641, Faculty of Health Sciences, University of Copenhagen
    • , M. PenkowaAffiliated withSection of Neuroprotection, Institute of Neuroscience and Pharmacology, the Panum Institute, Faculty of Health Sciences, University of Copenhagen
    • , P. HojmanAffiliated withThe Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC, Rigshospitalet—Section 7641, Faculty of Health Sciences, University of Copenhagen
    • , A. ZankariAffiliated withThe Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC, Rigshospitalet—Section 7641, Faculty of Health Sciences, University of Copenhagen
    • , M. J. WattAffiliated withBiology of Lipid Metabolism Group, Department of Physiology, Monash University
    • , H. BruunsgaardAffiliated withThe Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC, Rigshospitalet—Section 7641, Faculty of Health Sciences, University of Copenhagen
    • , B. K. PedersenAffiliated withThe Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC, Rigshospitalet—Section 7641, Faculty of Health Sciences, University of Copenhagen Email author 
    • , M. A. FebbraioAffiliated withCellular and Molecular Metabolism Laboratory, Diabetes and Metabolism Division, Baker Heart Research Institute Email author 

Abstract

Aims/hypothesis

Brain-derived neurotrophic factor (BDNF) is produced in skeletal muscle, but its functional significance is unknown. We aimed to determine the signalling processes and metabolic actions of BDNF.

Methods

We first examined whether exercise induced BDNF expression in humans. Next, C2C12 skeletal muscle cells were electrically stimulated to mimic contraction. L6 myotubes and isolated rat extensor digitorum longus muscles were treated with BDNF and phosphorylation of the proteins AMP-activated protein kinase (AMPK) (Thr172) and acetyl coenzyme A carboxylase β (ACCβ) (Ser79) were analysed, as was fatty acid oxidation (FAO). Finally, we electroporated a Bdnf vector into the tibialis cranialis muscle of mice.

Results

BDNF mRNA and protein expression were increased in human skeletal muscle after exercise, but muscle-derived BDNF appeared not to be released into the circulation. Bdnf mRNA and protein expression was increased in muscle cells that were electrically stimulated. BDNF increased phosphorylation of AMPK and ACCβ and enhanced FAO both in vitro and ex vivo. The effect of BDNF on FAO was AMPK-dependent, since the increase in FAO was abrogated in cells infected with an AMPK dominant negative adenovirus or treated with Compound C, an inhibitor of AMPK. Electroporation of a Bdnf expression vector into the tibialis cranialis muscle resulted in increased BDNF protein production and tropomyosin-related kinase B (TrkBTyr706/707) and extracellular signal-regulated protein kinase (p44/42 Thr202/Tyr204) phosphorylation in these muscles. In addition, phosphorylation of ACCβ was markedly elevated in the Bdnf electroporated muscles.

Conclusions/interpretation

These data identify BDNF as a contraction-inducible protein in skeletal muscle that is capable of enhancing lipid oxidation in skeletal muscle via activation of AMPK.

Keywords

Cytokines Lipid metabolism Metabolism Neuropeptides Physical activity