Open AccessChronic TrkB agonist treatment in old age does not mitigate diaphragm neuromuscular dysfunction
Author(s) -
Greising Sarah M.,
Vasdev Amrit K.,
Zhan WenZhi,
Sieck Gary C.,
Mantilla Carlos B.
Publication year - 2017
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.13103
Subject(s) - tropomyosin receptor kinase b , sarcopenia , medicine , neuromuscular transmission , diaphragm (acoustics) , neuromuscular junction , agonist , muscle atrophy , neurotrophic factors , endocrinology , brain derived neurotrophic factor , skeletal muscle , neuroscience , receptor , biology , physics , acoustics , loudspeaker
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 Trk B F616A mice ( n = 32) were randomized to the following 6‐month treatment groups: vehicle‐control, 7,8‐ DHF , and 7,8‐ DHF and 1 NMPP 1 (an inhibitor of TrkB kinase activity in Trk B F616A 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.