TrkB Signaling Contributes to Transdiaphragmatic Pressure Generation in Aged Mice

2021 ◽  
Author(s):  
Miguel Pareja-Cajiao ◽  
Heather M. Gransee ◽  
Gary C. Sieck ◽  
Carlos B. Mantilla
Keyword(s):  
Old Age ◽  
Neuromuscular Transmission ◽  
Systemic Treatment ◽  
Diaphragm Muscle ◽  
Aging Effects ◽  
Phrenic Nerve Stimulation ◽  
Transdiaphragmatic Pressure ◽  
Neuromuscular Dysfunction ◽  
Breathing Room ◽  
Old 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 (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 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 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 (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 (~7 cm H2O) to occlusion and sighs (~25 cm H2O), with no differences across treatments. Pdimax 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.

Diaphragmatic failure during loaded breathing: role of neuromuscular transmission

1993 ◽  
Vol 74 (4) ◽  
pp. 1679-1683 ◽  
Author(s):  
A. R. Bazzy ◽  
D. F. Donnelly
Keyword(s):  
Phrenic Nerve ◽  
Neuromuscular Transmission ◽  
Diaphragm Muscle ◽  
Plateau Phase ◽  
Nerve Activity ◽  
Transdiaphragmatic Pressure ◽  
M Wave ◽  
Arterial Pco2 ◽  
Loaded Breathing

To determine whether central or peripheral mechanisms are responsible for diaphragmatic failure during loaded breathing, phrenic nerve activity (iENG), diaphragm muscle electromyogram (iEMG), and transdiaphragmatic pressure (Pdi) were measured in unanesthetized chronically instrumented sheep during inspiratory flow-resistive (IFR) loaded breathing. After placement of the IFR load, Pdi increased initially and remained relatively stable for 10–30 min [Pdi = 69.9 +/- 6.3 (SE) cmH2O, n = 6]; arterial PCO2 also increased from baseline (35.8 +/- 0.9 Torr) to 55.1 +/- 4.7 Torr. During IFR loading, iEMG and iENG also increased from baseline, but during the plateau phase of Pdi, iENG continued to increase at the same time while iEMG was stable, and the M wave, evoked by phrenic nerve stimulation, decreased during this period. After the plateau phase, Pdi decreased and arterial PCO2 increased, at which point the study was terminated (at 82.1 +/- 20.6 min). The observation that iENG increased while Pdi and iEMG were stable demonstrates a reduced efficiency of neuromuscular transmission and suggests that the neuromuscular junction is an important site of diaphragmatic failure in unanesthetized sheep during IFR loaded breathing.

scholarly journals Inhibition of TrkB kinase activity impairs transdiaphragmatic pressure generation

2020 ◽  
Vol 128 (2) ◽  
pp. 338-344
Author(s):  
Miguel Pareja-Cajiao ◽  
Heather M. Gransee ◽  
Naomi A. Cole ◽  
Gary C. Sieck ◽  
Carlos B. Mantilla
Keyword(s):  
Neuromuscular Transmission ◽  
Kinase Activity ◽  
Motor Units ◽  
Diaphragm Muscle ◽  
Receptor Subtype ◽  
Transdiaphragmatic Pressure ◽  
Tracheal Occlusion ◽  
Motor Behaviors ◽  
Subtype B ◽  
Maximal Stimulation

Signaling via the tropomyosin-related kinase receptor subtype B (TrkB) regulates neuromuscular transmission, and inhibition of TrkB kinase activity by 1NMPP1 in TrkBF616A 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 TrkBF616A mice 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 & NOTEWORTHY 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.

scholarly journals Diaphragm Neuromuscular Transmission Failure in a Mouse Model of an Early-Onset Neuromotor Disorder

2020 ◽  
Author(s):  
Matthew J. Fogarty ◽  
Joline E. Brandenburg ◽  
Gary C. Sieck
Keyword(s):  
Motor Neurons ◽  
Nerve Stimulation ◽  
Phrenic Nerve ◽  
Early Onset ◽  
Neuromuscular Transmission ◽  
Postnatal Period ◽  
Diaphragm Muscle ◽  
Phrenic Nerve Stimulation ◽  
Transmission Failure ◽  
S Period

The spa transgenic mouse displays spasticity and hypertonia that develops during the early postnatal period, with motor impairments that are remarkably similar to symptoms of human cerebral palsy. Previously, we observed that spa mice have fewer phrenic motor neurons innervating the diaphragm muscle (DIAm). We hypothesize that spa mice exhibit increased susceptibility to neuromuscular transmission failure (NMTF) due to an expanded innervation ratio. We retrogradely-labeled phrenic motor neurons with rhodamine and imaged them in horizontal sections (70 µm) using confocal microscopy. Phrenic nerve-DIAm strip preparations from wildtype and spa mice were stretched to optimal length, and force was evoked by phrenic nerve stimulation at 10, 40 or 75 Hz in 330 ms duration trains repeated each s (33% duty cycle) across a 120 s period. To assess NMTF, force evoked by phrenic nerve stimulation was compared to force evoked by direct DIAm stimulation superimposed every 15 s. Total DIAm fiber number was estimated in hematoxylin and eosin stained strips. Compared to wildtype, spa mice had over two-fold greater NMTF during the first stimulus train that persisted throughout the 120 s period of repetitive activation. In both wildtype and spa mice, NMTF was stimulation-frequency dependent. There was no difference in neuromuscular junction morphology or the total number of DIAm fibers between wildtype and spa mice, however there was an increase innervation ratio (39%) in spa mice. We conclude that early-onset developmental neuromotor disorders impair the efficacy of DIAm neuromuscular transmission, likely to contribute to respiratory complications.

scholarly journals Exercise-induced alterations and loss of sarcomeric M-line organization in the diaphragm muscle of obscurin knockout mice

2017 ◽  
Vol 312 (1) ◽  
pp. C16-C28 ◽  
Author(s):  
D. Randazzo ◽  
B. Blaauw ◽  
C. Paolini ◽  
E. Pierantozzi ◽  
S. Spinozzi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Fibers ◽  
Detailed Examination ◽  
Diaphragm Muscle ◽  
Hindlimb Muscles ◽  
Skeletal Muscle Fibers ◽  
Exercise Induced ◽  
Old Mice ◽  
Ankyrin B ◽  
Deficient Mice

We recently reported that skeletal muscle fibers of obscurin knockout (KO) mice present altered distribution of ankyrin B (ankB), disorganization of the subsarcolemmal microtubules, and reduced localization of dystrophin at costameres. In addition, these mice have impaired running endurance and increased exercise-induced sarcolemmal damage compared with wild-type animals. Here, we report results from a combined approach of physiological, morphological, and structural studies in which we further characterize the skeletal muscles of obscurin KO mice. A detailed examination of exercise performance, using different running protocols, revealed that the reduced endurance of obscurin KO animals on the treadmill depends on exercise intensity and age. Indeed, a mild running protocol did not evidence significant differences between control and obscurin KO mice, whereas comparison of running abilities of 2-, 6-, and 11-mo-old mice exercised at exhaustion revealed a progressive age-dependent reduction of the exercise tolerance in KO mice. Histological analysis indicated that heavy exercise induced leukocyte infiltration, fibrotic connective tissue deposition, and hypercontractures in the diaphragm of KO mice. On the same line, electron microscopy revealed that, in the diaphragm of exercised obscurin KO mice, but not in the hindlimb muscles, both M-line and H-zone of sarcomeres appeared wavy and less defined. Altogether, these results suggest that obscurin is required for the maintenance of morphological and ultrastructural integrity of skeletal muscle fibers against damage induced by intense mechanical stress and point to the diaphragm as the skeletal muscle most severely affected in obscurin-deficient mice.

scholarly journals Protein of youth (adventure of a sensation)

2018 ◽  
pp. 78-83
Author(s):  
А.А. Пальцын
Keyword(s):  
Growth Factors ◽  
Old Age ◽  
Skeletal Muscles ◽  
Scientific Community ◽  
Harvard University ◽  
Transforming Growth Factors ◽  
Tissue Concentrations ◽  
Mammalian Blood ◽  
Old Mice ◽  
Reliable Methods

Группа исследователей из Гарвардского университета в 2013 и последующих годах опубликовала серию статей об одном из трансформирующих факторов роста b - GDF-11. По данным этого коллектива, концентрация GDF-11 в крови и тканях млекопитающих с возрастом снижается. Искусственное повышение содержания GDF-11 у старых мышей путем ежедневных инъекций рекомбинантного GDF-11 или парабиоза в течение месяца с молодыми мышами существенно снижало и даже устраняло свойственные старости неблагоприятные изменения сердца, скелетных мышц, мозга. Статьи Гарвардской группы привлекли большое внимание научного сообщества, были комментированы в сотнях публикаций, и в них GDF-11 стали часто называть белком молодости. Капитальность заявки Гарварда стимулировала капитальность проверочных экспериментов с привлечением максимально надежных методик. Эти эксперименты расширили знания о GDF-11, но не подтвердили его права называться белком молодости. A research group at the Harvard University in 2013 and the next years has published a series of articles focusing on one of transforming growth factors b, GDF-11. According to these reports mammalian blood and tissue concentrations of GDF-11 decrease with age. Increasing the GDF-11 content in old mice using daily injections of recombinant GDF-11 or one-month parabiosis induced in young mice significantly reduced and even eliminated adverse, old age-specific changes in the heart, skeletal muscles, and brain. The reports of the Harvard group have attracted much attention of the scientific community, and were cited in hundreds of publications where GDF-11 was often called the protein of youth. The solidity of the Harvard team statement warranted solidity of test experiments, which used the most reliable methods. These experiments have expanded the knowledge of GDF-11 but did not confirm its right to be called a protein of youth.

Effect of digitalis on the diaphragm in anesthetized dogs

1987 ◽  
Vol 63 (1) ◽  
pp. 277-284 ◽  
Author(s):  
Y. Kikuchi ◽  
W. Hida ◽  
C. Shindoh ◽  
T. Chonan ◽  
H. Miki ◽  
...  
Keyword(s):  
Nerve Stimulation ◽  
Phrenic Nerve ◽  
Stimulus Frequency ◽  
Dependent Manner ◽  
Phrenic Nerve Stimulation ◽  
Transdiaphragmatic Pressure ◽  
Mechanically Ventilated ◽  
Before And After ◽  
Residual Capacity ◽  
Anesthetized Dogs

We examined the effect of digitalis on diaphragmatic contractility and fatigability in 19 anesthetized mechanically ventilated dogs. The diaphragmatic force was assessed from transdiaphragmatic pressure (Pdi) developed at functional residual capacity against an occluded airway during cervical phrenic nerve stimulation. In a first group of five dogs, Pdi-stimulus frequency relationships were compared before and after administration of ouabain in doses of 0.01, 0.02, and 0.04 mg/kg. In a second group, diaphragmatic fatigue was produced by bilateral phrenic nerve stimulation at 30 Hz. Ten seconds of stimulation and 15 s of mechanical ventilation were repeated for 30 min. The rates of decrease in Pdi were compared between two groups, one of 0.05 mg/kg deslanoside-treated dogs (n = 7) and one of nontreated dogs (n = 7). After ouabain administration Pdi was significantly greater at each frequency in a dose-dependent manner. On the other hand, the rate of decrease in Pdi in the deslanoside group was significantly smaller than that in the nontreated group, whereas deslanoside did not greatly change the Pdi-frequency curves in fresh diaphragm. We conclude that ouabain improves contractility of the fresh diaphragm and that deslanoside has a protective effect against fatigability.

scholarly journals Diaphragm neuromuscular transmission failure in aged rats

2019 ◽  
Vol 122 (1) ◽  
pp. 93-104 ◽  
Author(s):  
Matthew J. Fogarty ◽  
Maria A. Gonzalez Porras ◽  
Carlos B. Mantilla ◽  
Gary C. Sieck
Keyword(s):  
Nerve Stimulation ◽  
Phrenic Nerve ◽  
Neuromuscular Transmission ◽  
Motor Units ◽  
Diaphragm Muscle ◽  
Muscle Stimulation ◽  
Transmission Failure ◽  
Old Rats ◽  
Motor Neuron Loss ◽  
Fast Twitch

In aging Fischer 344 rats, phrenic motor neuron loss, neuromuscular junction abnormalities, and diaphragm muscle (DIAm) sarcopenia are present by 24 mo of age, with larger fast-twitch fatigue-intermediate (type FInt) and fast-twitch fatigable (type FF) motor units particularly vulnerable. We hypothesize that in old rats, DIAm neuromuscular transmission deficits are specific to type FInt and/or FF units. In phrenic nerve/DIAm preparations from rats at 6 and 24 mo of age, the phrenic nerve was supramaximally stimulated at 10, 40, or 75 Hz. Every 15 s, the DIAm was directly stimulated, and the difference in forces evoked by nerve and muscle stimulation was used to estimate neuromuscular transmission failure. Neuromuscular transmission failure in the DIAm was observed at each stimulation frequency. In the initial stimulus trains, the forces evoked by phrenic nerve stimulation at 40 and 75 Hz were significantly less than those evoked by direct muscle stimulation, and this difference was markedly greater in 24-mo-old rats. During repetitive nerve stimulation, neuromuscular transmission failure at 40 and 75 Hz worsened to a greater extent in 24-mo-old rats compared with younger animals. Because type IIx and/or IIb DIAm fibers (type FInt and/or FF motor units) display greater susceptibility to neuromuscular transmission failure at higher frequencies of stimulation, these data suggest that the age-related loss of larger phrenic motor neurons impacts nerve conduction to muscle at higher frequencies and may contribute to DIAm sarcopenia in old rats. NEW & NOTEWORTHY Diaphragm muscle (DIAm) sarcopenia, phrenic motor neuron loss, and perturbations of neuromuscular junctions (NMJs) are well described in aged rodents and selectively affect FInt and FF motor units. Less attention has been paid to the motor unit-specific aspects of nerve-muscle conduction. In old rats, increased neuromuscular transmission failure occurred at stimulation frequencies where FInt and FF motor units exhibit conduction failures, along with decreased apposition of pre- and postsynaptic domains of DIAm NMJs of these units.

scholarly journals Korean Red Ginseng Plays an Anti-Aging Role by Modulating Expression of Aging-Related Genes and Immune Cell Subsets

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1492 ◽  
Author(s):  
Kun Kuk Shin ◽  
Young-Su Yi ◽  
Jin Kyeong Kim ◽  
Haeyeop Kim ◽  
Mohammad Amjad Hossain ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Immune Cell ◽  
Serum Levels ◽  
Red Ginseng ◽  
Aging Effects ◽  
Thymic Involution ◽  
Korean Red Ginseng ◽  
Immune Cell Subsets ◽  
Underlying Mechanisms ◽  
Old Mice

Despite previous reports of anti-aging effects of Korean red ginseng (KRG), the underlying mechanisms remain poorly understood. Therefore, this study investigated possible mechanisms of KRG-mediated anti-aging effects in aged mice. KRG significantly inhibited thymic involution in old mice. Interestingly, KRG only increased protein expression, but not mRNA expression, of aging-related genes Lin28a, GDF-11, Sirt1, IL-2, and IL-17 in the thymocytes of old mice. KRG also modulated the population of some types of immune cells in old mice. KRG increased the population of regulatory T cells and interferon-gamma (IFN-γ)-expressing natural killer (NK) cells in the spleen of old mice, but serum levels of regulatory T cell-specific cytokines IL-10 and TGF-β were unaffected. Finally, KRG recovered mRNA expression of Lin28a, GDF-11, and Sirt1 artificially decreased by concanavalin A (Con A) in both thymocytes and splenocytes of old mice without cytotoxicity. These results suggest that KRG exerts anti-aging effects by preventing thymic involution, as well as modulating the expression of aging-related genes and immune cell subsets.

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