Chronic TrkB agonist treatment in old age does not mitigate diaphragm neuromuscular dysfunction

Sarah M. Greising, Amrit K. Vasdev, Wen Zhi Zhan, Gary C. Sieck, Carlos B. Mantilla

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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 TrkBF 616A mice (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 TrkBF 616A mice) 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.

Original languageEnglish (US)
Article numbere13103
JournalPhysiological Reports
Volume5
Issue number1
DOIs
StatePublished - Jan 1 2017

Bibliographical note

Funding Information:
This research was supported by grants from National Institute of Health R01-AG-044615 (CBM & GCS) and T32-HL105355 (SMG), and the Mayo Clinic.

Keywords

  • 7-8-dihydroxyflavone
  • Brain-derived neurotrophic factor
  • Neuromuscular transmission failure
  • Tropomyosin-related kinase

PubMed: MeSH publication types

  • Journal Article

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