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 BF 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 Trk BF 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.
Highlights
Age-related neuromuscular dysfunction and sarcopenia are evident in the diaphragm muscle (Greising et al 2013, 2015b, 2015c)
Contrary to our hypothesis that enhancing brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase receptor subtype B (TrkB) signaling with 7,8-DHF would mitigate age-related neuromuscular dysfunction, we found no effect of 7,8-DHF treatment on diaphragm neuromuscular transmission failure, muscle specific force, fiber cross-sectional areas or fiber type clustering, a surrogate marker for denervation
We previously showed that acute 7,8-DHF treatment improved diaphragm neuromuscular transmission failure induced by repetitive phrenic nerve stimulation in adult mice (Mantilla and Ermilov 2012), with effects similar to those previously shown for BDNF in adult rats (Mantilla et al 2004) and mice (Greising et al 2015a)
Summary
Age-related neuromuscular dysfunction and sarcopenia (i.e., muscle fiber atrophy and loss of force) are evident in the diaphragm muscle (Greising et al 2013, 2015b, 2015c). Impaired neuromuscular transmission in the diaphragm muscle occurs well before noticeable atrophy or force loss (Greising et al 2015a). A reduction in diaphragm muscle-specific force (force per cross-sectional area) is only evident by 24 months of age in mice (Greising et al 2013, 2015b, 2015c) and rats (Elliott et al 2016b), and there is atrophy of type IIx and/or IIb fibers in both species (Elliott et al 2016b).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
