title: 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.
abstract: OBJECTIVE
  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) (Thr(172)) and acetyl coenzyme A carboxylase beta (ACCbeta) (Ser(79)) 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 ACCbeta 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 (TrkB(Tyr706/707)) and extracellular signal-regulated protein kinase (p44/42 Thr(202)/Tyr(204)) phosphorylation in these muscles. In addition, phosphorylation of ACCbeta was markedly elevated in the Bdnf electroporated muscles.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Diabetes and Metabolism Division, Baker Heart Research Institute, St Kilda Road Central, Melbourne, Victoria 8008, Australia.
authors.forename: V B
authors.initials: VB
authors.lastname: Matthews
authors.forename: M-B
authors.initials: MB
authors.lastname: Aström
authors.forename: M H S
authors.initials: MH
authors.lastname: Chan
authors.forename: C R
authors.initials: CR
authors.lastname: Bruce
authors.forename: K S
authors.initials: KS
authors.lastname: Krabbe
authors.forename: O
authors.initials: O
authors.lastname: Prelovsek
authors.forename: T
authors.initials: T
authors.lastname: Akerström
authors.forename: C
authors.initials: C
authors.lastname: Yfanti
authors.forename: C
authors.initials: C
authors.lastname: Broholm
authors.forename: O H
authors.initials: OH
authors.lastname: Mortensen
authors.forename: M
authors.initials: M
authors.lastname: Penkowa
authors.forename: P
authors.initials: P
authors.lastname: Hojman
authors.forename: A
authors.initials: A
authors.lastname: Zankari
authors.forename: M J
authors.initials: MJ
authors.lastname: Watt
authors.forename: H
authors.initials: H
authors.lastname: Bruunsgaard
authors.forename: B K
authors.initials: BK
authors.lastname: Pedersen
authors.forename: M A
authors.initials: MA
authors.lastname: Febbraio
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D005080:Exercise Test; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005223:Fats / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology*; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D005223:Fats; D020813:Receptor, trkB; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase