Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, College of Medicine and Science, Rochester, Minnesota.
Department of Physiology and Biomedical Engineering, Mayo Clinic, College of Medicine and Science, Rochester, Minnesota.
J Appl Physiol (1985). 2020 Feb 1;128(2):338-344. doi: 10.1152/japplphysiol.00564.2019. Epub 2020 Jan 16.
Signaling via the tropomyosin-related kinase receptor subtype B (TrkB) regulates neuromuscular transmission, and inhibition of TrkB kinase activity by 1NMPP1 in mice worsens neuromuscular transmission failure (NMTF). We hypothesized that acute inhibition of TrkB kinase activity will impair the ability of the diaphragm muscle to produce maximal transdiaphragmatic pressure (Pdi) without impacting the ability to generate forces associated with ventilation, consistent with the greater susceptibility to NMTF in motor units responsible for higher-force nonventilatory behaviors. Adult male and female mice were injected with 1NMPP1 ( = 8) or vehicle (DMSO; = 8) 1 h before Pdi measurements during eupneic breathing, hypoxia/hypercapnia (10% O/5% CO), tracheal occlusion, spontaneous deep breaths ("sighs") and during maximal activation elicited by bilateral phrenic nerve stimulation. In the vehicle-treated group, Pdi increased from 10 cmHO during eupnea and hypoxia/hypercapnia, to ~35 cmHO during sighs and tracheal occlusion, and to ~65 cm HO during maximal stimulation. There was no effect of acute 1NMPP1 treatment on Pdi generated during most behaviors, except during maximal stimulation (30% reduction; < 0.05). This reduction in maximal Pdi is generally similar to the worsening of NMTF previously reported with TrkB kinase inhibition in rodents. Accordingly, impaired TrkB signaling limits the range of motor behaviors accomplished by the diaphragm muscle and may contribute to neuromuscular dysfunction, primarily by impacting fatigable, higher force-generating motor units. TrkB signaling plays an important role in maintaining neuromuscular function in the diaphragm muscle and may be necessary to accomplish the various motor behaviors ranging from ventilation to expulsive, behaviors requiring near-maximal forces. This study shows that inhibition of TrkB kinase activity impairs maximal pressure generation by the diaphragm muscle, but the ability to generate the lower pressures required for ventilatory behaviors is not impacted.
通过原肌球蛋白相关激酶受体亚型 B (TrkB) 的信号转导调节神经肌肉传递，而在小鼠中 1NMPP1 抑制 TrkB 激酶活性会加重神经肌肉传递衰竭 (NMTF)。我们假设急性抑制 TrkB 激酶活性会损害膈肌无力产生最大跨膈压 (Pdi) 的能力，而不会影响与通气相关的力的产生能力，这与负责更高力非通气行为的运动单位对 NMTF 的更大易感性一致。成年雄性和雌性 小鼠在进行最大膈神经刺激诱发的 Pdi 测量前 1 小时接受 1NMPP1（n = 8）或载体（DMSO；n = 8）注射，在正常通气呼吸、低氧/高碳酸血症（10% O/5% CO）、气管阻塞、自发性深呼吸（“叹息”）期间进行 Pdi 测量。在载体处理组中，Pdi 在正常通气和低氧/高碳酸血症期间从约 10 cmHO 增加，在叹息和气管阻塞期间增加到约 35 cmHO，在最大刺激期间增加到约 65 cmHO。急性 1NMPP1 处理对大多数行为期间产生的 Pdi 没有影响，除了在最大刺激期间（~30%减少；< 0.05）。这种最大 Pdi 的减少通常与先前在啮齿动物中 TrkB 激酶抑制时报道的 NMTF 恶化相似。因此，受损的 TrkB 信号传导限制了膈肌无力完成的运动行为范围，并可能导致神经肌肉功能障碍，主要是通过影响易疲劳、产生更高力的运动单位。TrkB 信号转导在维持膈肌无力方面起着重要作用，并且可能对于完成从通气到呼气等各种运动行为是必要的，这些行为需要接近最大的力。本研究表明，抑制 TrkB 激酶活性会损害膈肌无力产生最大压力的能力，但不会影响产生通气行为所需的较低压力的能力。
