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Physiol Rep. 2017 Jan;5(1). pii: e13103. doi: 10.14814/phy2.13103.

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

Author information

1
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
2
Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota.
3
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota mantilla.carlos@mayo.edu.

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 TrkBF616A 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 TrkBF616A 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.

KEYWORDS:

7‐8‐dihydroxyflavone; Brain‐derived neurotrophic factor; Neuromuscular transmission failure; Tropomyosin‐related kinase

PMID:
28082429
PMCID:
PMC5256161
DOI:
10.14814/phy2.13103
[Indexed for MEDLINE]
Free PMC Article

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