Ventilatory deficits are common in old age and may result from neuromuscular dysfunction. Signaling via the tropomyosin-related kinase receptor B (TrkB) regulates neuromuscular transmission and in young mice is important for the generation of transdiaphragmatic pressure (Pdi). Loss of TrkB signaling worsened neuromuscular transmission failure and reduced maximal Pdi, and these effects are similar to those observed in old age. Administration of TrkB agonists such as 7,8-dihydroxyflavone (7,8-DHF) improves neuromuscular transmission in young and old mice (18 months; 75% survival). We hypothesized that TrkB signaling contributes to Pdi generation in old mice, particularly during maximal force behaviors. Old male and female TrkB^F616A mice, with a mutation that induces 1NMPP1-mediated TrkB kinase inhibition, were randomly assigned to systemic treatment with vehicle, 7,8-DHF, or 1NMPP1 one hour prior to experiments. Pdi was measured during eupneic breathing (room air), hypoxia-hypercapnia (10% O₂/5% CO₂), tracheal occlusion, spontaneous deep breaths ("sighs"), and bilateral phrenic nerve stimulation (Pdi_max). There were no differences in the Pdi amplitude across treatments during ventilatory behaviors (eupnea, hypoxia-hypercapnia, occlusion or sigh). As expected, Pdi increased from eupnea and hypoxia-hypercapnia (~7 cm H₂O) to occlusion and sighs (~25 cm H₂O), with no differences across treatments. Pdi_max was ~50 cm H₂O in the vehicle and 7,8-DHF groups and ~40 cm H₂O in the 1NMPP1 group (F8,74 = 2; p = 0.02). Our results indicate that TrkB signaling is necessary for generating maximal forces by the diaphragm muscle in old mice, and are consistent with aging effects of TrkB signaling on neuromuscular transmission.

中文翻译：

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TrkB 信号传导有助于老年小鼠产生跨膈压力


通气不足在老年人中很常见，可能是神经肌肉功能障碍造成的。原肌球蛋白相关激酶受体 B (TrkB) 的信号传导可调节神经肌肉传递，在年轻小鼠中对于跨膈压力 (Pdi) 的产生非常重要。 TrkB 信号传导的丧失会加剧神经肌肉传递失败并降低最大 Pdi，这些影响与老年时观察到的类似。施用 TrkB 激动剂（例如 7,8-二羟基黄酮 (7,8-DHF)）可改善年轻和年老小鼠（18 个月；存活率 75%）的神经肌肉传递。我们假设 TrkB 信号传导有助于老年小鼠 Pdi 的产生，特别是在最大力量行为期间。具有诱导 1NMPP1 介导的 TrkB 激酶抑制的突变的老年雄性和雌性 TrkB ^F616A小鼠在实验前一小时被随机分配接受媒介物、7,8-DHF 或 1NMPP1 全身治疗。 Pdi 是在平静呼吸（室内空气）、缺氧高碳酸血症（10% O ₂ /5% CO ₂ ）、气管阻塞、自发深呼吸（“叹气”）和双侧膈神经刺激（Pdi _max ）期间测量的。在通气行为（平静、缺氧-高碳酸血症、闭塞或叹气）期间，不同治疗期间的 Pdi 幅度没有差异。正如预期的那样，Pdi 从平静呼吸和缺氧高碳酸血症 (~7 cm H ₂ O) 增加到闭塞和叹息 (~25 cm H ₂ O)，且治疗之间没有差异。媒介物和7,8-DHF组中的Pdi _max为约50cm H ₂ O，1NMPP1组中的Pdi max为约40cm H ₂ O(F8,74 = 2；p = 0.02)。 我们的结果表明，TrkB 信号传导对于老年小鼠的膈肌产生最大力量是必要的，并且与 TrkB 信号传导对神经肌肉传递的衰老影响一致。