title: Ageing and neurotrophic signalling effects on diaphragm neuromuscular function.
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.
authors: Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors: Sarah M
authors: SM
authors: Greising
authors: Leonid G
authors: LG
authors: Ermilov
authors: Gary C
authors: GC
authors: Sieck
authors: Carlos B
authors: CB
authors: Mantilla
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology*; D003964:Diaphragm / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D009119:Muscle Contraction; D009154:Mutation; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C582212:1NMPP1 compound; D019208:Brain-Derived Neurotrophic Factor; D011720:Pyrazoles; D011743:Pyrimidines; D020813:Receptor, trkB
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