Inhibition of TrkB kinase activity impairs transdiaphragmatic pressure generation.
Inhibition of TrkB kinase activity impairs transdiaphragmatic pressure generation.
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抑制 TrkB 激酶活性会损害跨膈压力的产生。
DOI：
10.1152/japplphysiol.00564.2019
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Mantilla,CarlosB
中科院分区：
文献类型：
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作者：
Pareja-Cajiao,Miguel;Gransee,HeatherM;Cole,NaomiA;Sieck,GaryC;Mantilla,CarlosB
通过原肌球蛋白相关激酶受体 B 亚型 (TrkB) 的信号传导可调节神经肌肉传递，TrkBF616Amice 中 1NMPP1 抑制 TrkB 激酶活性会加重神经肌肉传递失败 (NMTF)。我们假设，TrkB 激酶活性的急性抑制将损害膈肌产生最大跨膈压 (Pdi) 的能力，而不影响产生与通气相关的力的能力，这与负责高力非通气行为的运动单位对 NMTF 的更大敏感性一致。成年雄性和雌性 TrkBF616Amice 在 Pdi 测量前 1 小时，在平静呼吸、缺氧/高碳酸血症 (10% O2/5% CO2)、气管阻塞、自发深呼吸（“叹气”）以及双侧膈神经刺激引起的最大激活期间注射 1NMPP1 (n= 8) 或媒介物 (DMSO;n= 8)。在媒介物治疗组中，Pdi 从平静呼吸和缺氧/高碳酸血症期间的约 10 cmH2O 增加到叹气和气管阻塞期间的约 35 cmH2O，以及最大刺激期间的约 65 cmH2O。除最大刺激期间外，急性 1NMPP1 治疗对大多数行为中产生的 Pdi 没有影响（减少约 30%；P<0.05）。这种最大 Pdi 的降低通常与先前报道的啮齿类动物 TrkB 激酶抑制导致的 NMTF 恶化相似。因此，受损的 TrkB 信号传导限制了膈肌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、产生较高力量的运动单位。新的和值得注意的 TrkB 信号传导在维持膈肌的神经肌肉功能方面发挥着重要作用，并且可能是完成从通气到排出的各种运动行为所必需的，这些行为需要接近最大的力量。这项研究表明，抑制 TrkB 激酶活性会损害膈肌产生的最大压力，但产生通气行为所需较低压力的能力不会受到影响。
Signaling via the tropomyosin-related kinase receptor subtype B (TrkB) regulates neuromuscular transmission, and inhibition of TrkB kinase activity by 1NMPP1 inTrkBF616Amice 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 femaleTrkBF616Amice were injected with 1NMPP1 (n= 8) or vehicle (DMSO;n= 8) 1 h before Pdi measurements during eupneic breathing, hypoxia/hypercapnia (10% O2/5% CO2), 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 cmH2O during eupnea and hypoxia/hypercapnia, to ~35 cmH2O during sighs and tracheal occlusion, and to ~65 cm H2O during maximal stimulation. There was no effect of acute 1NMPP1 treatment on Pdi generated during most behaviors, except during maximal stimulation (~30% reduction;P< 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.NEW & NOTEWORTHYTrkB 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.