PMID- 26517952 OWN - NLM STAT- MEDLINE DCOM- 20160908 LR - 20181113 IS - 1873-6815 (Electronic) IS - 0531-5565 (Print) IS - 0531-5565 (Linking) VI - 72 DP - 2015 Dec TI - Role of TrkB kinase activity in aging diaphragm neuromuscular junctions. PG - 184-91 LID - S0531-5565(15)30075-9 [pii] LID - 10.1016/j.exger.2015.10.013 [doi] AB - 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. CI - Copyright (c) 2015 Elsevier Inc. All rights reserved. FAU - Greising, Sarah M AU - Greising SM AD - Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. FAU - Stowe, Jessica M AU - Stowe JM AD - Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. FAU - Sieck, Gary C AU - Sieck GC AD - 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. FAU - Mantilla, Carlos B AU - Mantilla CB AD - 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. LA - eng GR - R01 AG044615/AG/NIA NIH HHS/United States GR - T32 HL105355/HL/NHLBI NIH HHS/United States GR - R01-AG044615/AG/NIA NIH HHS/United States GR - T32-HL105355/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151027 PL - England TA - Exp Gerontol JT - Experimental gerontology JID - 0047061 RN - 0 (1NMPP1 compound) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Pyrazoles) RN - 0 (Pyrimidines) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM MH - Aging/*drug effects MH - Animals MH - Brain-Derived Neurotrophic Factor/genetics/*metabolism MH - Denervation MH - Diaphragm/innervation MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Neuromuscular Junction/*drug effects MH - Pyrazoles/*chemistry MH - Pyrimidines/*chemistry MH - Receptor, trkB/antagonists & inhibitors/genetics/*metabolism MH - Signal Transduction/*drug effects PMC - PMC4667365 MID - NIHMS734967 OTO - NOTNLM OT - Brain derived neurotrophic factor OT - Denervation OT - Innervation OT - Motor unit OT - Tropomyosin-related kinase receptor subtype B COIS- Disclosures The authors declare no conflict of interest. EDAT- 2015/11/01 06:00 MHDA- 2016/09/09 06:00 PMCR- 2016/12/01 CRDT- 2015/11/01 06:00 PHST- 2015/07/31 00:00 [received] PHST- 2015/10/23 00:00 [revised] PHST- 2015/10/26 00:00 [accepted] PHST- 2015/11/01 06:00 [entrez] PHST- 2015/11/01 06:00 [pubmed] PHST- 2016/09/09 06:00 [medline] PHST- 2016/12/01 00:00 [pmc-release] AID - S0531-5565(15)30075-9 [pii] AID - 10.1016/j.exger.2015.10.013 [doi] PST - ppublish SO - Exp Gerontol. 2015 Dec;72:184-91. doi: 10.1016/j.exger.2015.10.013. Epub 2015 Oct 27.