Acute Impact of Disrupting BDNF/TrkB Signaling on Diaphragm Muscle Force Generation across Motor Behaviors

Abstract

Brain‐derived neurotrophic factor (BDNF) binds with high affinity to tropomyosin‐related kinase receptor subtype B (TrkB), and plays an important role in neuromuscular junction (NMJ) function (regulating neuromuscular transmission and muscle innervation). We previously showed impaired neuromuscular transmission following acute inhibition of TrkB kinase activity in TrkBF616A mice harboring a point mutation that renders the kinase domain susceptible to inhibition by 1NMPP1 treatment. Neuromuscular transmission failure is expected to predominantly affect the ability of more fatigable motor units to generate force and thus primarily impair higher force motor behaviors. Accordingly, we hypothesized that acute administration of 1NMPP1 will impair the ability of the diaphragm muscle to accomplish higher force behaviors in adult, 6‐month old TrkBF616A mice. Transdiaphragmatic pressure (Pdi) measurements were conducted across a range of motor behaviors in lightly anesthetized mice during eupnea, exposure to hypoxia (10% O2)/hypercapnia (5% CO2), tracheal occlusion, spontaneous deep breaths (“sighs”) and during maximal activation elicited by bilateral phrenic nerve stimulation. Adult male and female TrkBF616A mice at 6 months were injected with 1NMPP1 or vehicle (DMSO) one hour prior to Pdi measurements. The Pdi generated during eupnea and hypoxia/hypercapnia was ~8 cm H20 compared to ~70 cm H20 during maximal stimulation. There was a significant reduction in Pdi during maximal force with bilateral phrenic nerve stimulation in the 1NMPP1 group compared to the vehicle control (p=0.01). There was no effect of 1NMPP1 on Pdi during eupnea, hypoxia/hypercapnia, tracheal occlusion, or sigh behaviors. The reduction in Pdi is generally similar to the impairment in neuromuscular transmission consistent with a predominant effect on motor units innervating fast‐twitch fatigable muscle fibers in the diaphragm muscle. Thus, impaired trophic BDNF/TrkB signaling can be expected to limit the range of motor behaviors accomplished by the diaphragm muscle and may be an important contributor to neuromuscular dysfunction.Support or Funding InformationThis study was supported by NIH grant R01 AG057052.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.