TrkB signaling contributes to transdiaphragmatic pressure generation in aged mice

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 (18mo; 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 1 h before experiments. Pdi was measured during eupneic breathing (room air), hypoxia-hypercapnia (10% O-2/5% 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 (similar to 7cm H2O) to occlusion and sighs (similar to 25 cm H2O), with no differences across treatments. Pdimax was similar to 50cm H2O in the vehicle and 7,8-DHF groups and similar to 40cm H2O in the 1NMPP1 group (F-8,F-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. NEW & NOTEWORTHY TrkB signaling is necessary for generating maximal forces by the diaphragm muscle. In 19- to 21-mo-old TrkBF616A mice susceptible to 1NMPP1-induced inhibition of TrkB kinase activity, maximal Pdi generated by bilateral phrenic nerve stimulation was similar to 20% lower after 1NMPP1 compared with vehicle-treated mice. Treatment with the TrkB agonist 7,8-dihydroxyflavone did not affect Pdi generation when compared with age-matched mice. Inhibition of TrkB kinase activity did not affect the forces generated during lower force behaviors in old age.

Automated summary

The results suggest that TrkB signaling is essential for generating maximal forces by the diaphragm muscle in old mice, consistent with the effects of aging on neuromuscular transmission. In older TrkBF616A mice with inhibited TrkB kinase activity, maximal Pdi was found to be about 20% lower compared to vehicle-treated mice. Treatment with the TrkB agonist 7,8-dihydroxyflavone did not have an impact on Pdi generation in old age.