Ageing and neurotrophic signalling effects on diaphragm neuromuscular function

J Physiol. 2015 Jan 15;593(2):431-40. doi: 10.1113/jphysiol.2014.282244. Epub 2014 Dec 1.

Abstract

The age-related mechanisms underlying sarcopenia are largely unknown. We hypothesize that age-related neuromuscular changes depend on brain-derived neurotrophic factor (BDNF) acting through the tropomyosin-related kinase receptor B (TrkB). Maximal specific force and neuromuscular transmission failure were assessed at 6, 18 and 24 months following control, BDNF or phosphoprotein phosphatase 1 derivative (1NMPP1) treatment in male TrkB(F616A) mice. Phosphoprotein phosphatase-1 derivatives such as 1NMPP1 inhibit TrkB kinase activity as a result of this single amino acid mutation in the ATP binding domain. Maximal twitch and isometric tetanic force were reduced at 24 months compared to 6 and 18 months (P < 0.001). Neuromuscular transmission failure significantly increased at 18 and 24 months compared to 6 months (age × treatment interaction: P < 0.001). Neuromuscular transmission was improved following BDNF at 6 and 18 months and was impaired only at 6 months following 1NMPP1 treatment. Age and inhibition of TrkB kinase activity had similar effects on neuromuscular transmission failure, supporting a critical role for BDNF/TrkB signalling on neuromuscular changes in ageing. These results suggest that an age-related loss of endogenous BDNF precedes reductions in TrkB kinase activity in the diaphragm muscle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism*
  • Aging / physiology
  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Brain-Derived Neurotrophic Factor / pharmacology*
  • Diaphragm / drug effects
  • Diaphragm / growth & development
  • Diaphragm / metabolism*
  • Diaphragm / physiology
  • Male
  • Mice
  • Muscle Contraction*
  • Mutation
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Receptor, trkB / genetics
  • Receptor, trkB / metabolism
  • Signal Transduction*

Substances

  • 1NMPP1 compound
  • Brain-Derived Neurotrophic Factor
  • Pyrazoles
  • Pyrimidines
  • Receptor, trkB