title: Role of TrkB kinase activity in aging diaphragm neuromuscular junctions.
abstract: Brain derived neurotrophic factor (BDNF) acting through the tropomyosin-related kinase receptor B (TrkB) enhances neuromuscular transmission in the diaphragm muscle of adult mice, reflecting presynaptic effects. With aging, BDNF enhancement of neuromuscular transmission is lost. We hypothesize that disrupting BDNF/TrkB signaling in early old age will reveal a period of susceptibility evident by morphological changes at neuromuscular junctions (NMJ). Adult, male TrkB(F616A) mice (n=25) at 6 and 18 months of age, were used to examine the structural properties of diaphragm muscle NMJs (n=1097). Confocal microscopy was used to compare pre- and post-synaptic morphology and denervation following a 7 day treatment with the phosphoprotein phosphatase-1 derivative 1NMPP1, which inhibits TrkB kinase activity in TrkB(F616A) mice vs. vehicle treatment. In early old age (18 months), presynaptic terminal volume decreased compared to 6 month old diaphragm NMJs (~20%). Inhibition of TrkB kinase activity significantly decreased the presynaptic terminal volume (~20%) and motor end-plate 2D planar area (~10%), independent of age group. Inhibition of TrkB kinase activity in early old age significantly reduced overlap of pre- and post-synaptic structures and increased the proportion of denervated NMJs (to ~20%). Collectively these results support a period of susceptibility in early old age when BDNF/TrkB signaling at diaphragm NMJs supports the maintenance of NMJs structure and muscle innervation.
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Greising
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Stowe
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Sieck
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Electronic address: mantilla.carlos@mayo.edu.
authors.forename: Carlos B
authors.initials: CB
authors.lastname: Mantilla
mesh_terms: D000375:Aging / Q000187:drug effects*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D003714:Denervation; D003964:Diaphragm / Q000294:innervation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009469:Neuromuscular Junction / Q000187:drug effects*; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C582212:1NMPP1 compound; D019208:Brain-Derived Neurotrophic Factor; D011720:Pyrazoles; D011743:Pyrimidines; D020813:Receptor, trkB
keywords: Brain derived neurotrophic factor; Denervation; Innervation; Motor unit; Tropomyosin-related kinase receptor subtype B