title: Chronic TrkB agonist treatment in old age does not mitigate diaphragm neuromuscular dysfunction.
abstract: Previously, we found that brain-derived neurotrophic factor (BDNF) signaling through the high-affinity tropomyosin-related kinase receptor subtype B (TrkB) enhances neuromuscular transmission in the diaphragm muscle. However, there is an age-related loss of this effect of BDNF/TrkB signaling that may contribute to diaphragm muscle sarcopenia (atrophy and force loss). We hypothesized that chronic treatment with 7,8-dihydroxyflavone (7,8-DHF), a small molecule BDNF analog and TrkB agonist, will mitigate age-related diaphragm neuromuscular transmission failure and sarcopenia in old mice. Adult male TrkBF616Amice (n = 32) were randomized to the following 6-month treatment groups: vehicle-control, 7,8-DHF, and 7,8-DHF and 1NMPP1 (an inhibitor of TrkB kinase activity in TrkBF616Amice) cotreatment, beginning at 18 months of age. At 24 months of age, diaphragm neuromuscular transmission failure, muscle-specific force, and fiber cross-sectional areas were compared across treatment groups. The results did not support our hypothesis in that chronic 7,8-DHF treatment did not improve diaphragm neuromuscular transmission or mitigate diaphragm muscle sarcopenia. Taken together, these results do not exclude a role for BDNF/TrkB signaling in aging-related changes in the diaphragm muscle, but they do not support the use of 7,8-DHF as a therapeutic agent to mitigate age-related neuromuscular dysfunction.
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Greising
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: Amrit K
authors.initials: AK
authors.lastname: Vasdev
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: Wen-Zhi
authors.initials: WZ
authors.lastname: Zhan
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.|Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Sieck
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota mantilla.carlos@mayo.edu.|Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Carlos B
authors.initials: CB
authors.lastname: 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 / Q000294:innervation* / Q000503:physiopathology; D047309:Flavones / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D020511:Neuromuscular Junction Diseases / Q000188:drug therapy / Q000503:physiopathology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D020813:Receptor, trkB / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D055948:Sarcopenia / Q000473:pathology; D015398:Signal Transduction
chemical_list: C479693:1-tert-butyl-3-naphthalen-1-ylmethyl-1H-pyrazolo(3,4-d)pyrimidin-4-ylemine; C485383:6,7-dihydroxyflavone; D019208:Brain-Derived Neurotrophic Factor; D047309:Flavones; D011720:Pyrazoles; D011743:Pyrimidines; D020813:Receptor, trkB
keywords: 7‐8‐dihydroxyflavone; Brain‐derived neurotrophic factor; Neuromuscular transmission failure; Tropomyosin‐related kinase