TrkB signaling contributes to transdiaphragmatic pressure generation in aged mice

Miguel Pareja-Cajiao, Heather M. Gransee, Gary C. Sieck, Carlos B. Mantilla

Research output: Contribution to journalArticlepeer-review

Abstract

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 TrkBF616A 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% O2/5% CO2), tracheal occlusion, spontaneous deep breaths (“sighs”), and bilateral phrenic nerve stimulation (Pdimax). 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 (~7cm H2O) to occlusion and sighs (~25cm H2O), with no differences across treatments. Pdimax was ~50cm H2O in the vehicle and 7,8-DHF groups and ~40cm 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. 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 ~20% lower after 1NMPP1 compared with vehicle-treated mice. Treatment with the TrkB agonist 7,8-dihydroxyfla-vone 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.

Original languageEnglish (US)
Pages (from-to)1157-1163
Number of pages7
JournalJournal of neurophysiology
Volume125
Issue number4
DOIs
StatePublished - Apr 2021

Keywords

  • Aging
  • Breathing
  • Diaphragm muscle
  • Neuromuscular transmission
  • Neurotrophins

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology

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