Chronic TrkB agonist treatment in old age does not mitigate diaphragm neuromuscular dysfunction

Greising, Sarah M.; Vasdev, Amrit; Zhan, Wen Zhi; Sieck, Gary C.; Mantilla, Carlos B.

doi:10.14814/phy2.13103

Cited by 21 publications

(11 citation statements)

References 59 publications

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“…During aging, the availability of TrkB receptors appears to decline in DIAm motor units (Greising et al. 2015b, ), although fiber‐type‐specific effects are currently unknown. Inhibiting TrkB signaling in young adult rodents results in neuromuscular transmission failure and neuromuscular junction defects at type IIx and/or IIb fibers (Mantilla et al.…”

Section: Discussionmentioning

confidence: 99%

Impact of aging on diaphragm muscle function in male and female Fischer 344 rats

et al. 2018

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The diaphragm muscle (DIAm) is the primary inspiratory muscle in mammals and is active during ventilatory behaviors, but it is also involved in higher‐force behaviors such as those necessary for clearing the airway. Our laboratory has previously reported DIAm sarcopenia in rats and mice characterized by DIAm atrophy and a reduction in maximum specific force at 24 months of age. In Fischer 344 rats, these studies were limited to male animals, although in other studies, we noted a more rapid increase in body mass from 6 to 24 months of age in females (~140%) compared to males (~110%). This difference in body weight gain suggests a possible sex difference in the manifestation of sarcopenia. In mice, we previously measured transdiaphragmatic pressure (Pdi) to evaluate in vivo DIAm force generation across a range of motor behaviors, but found no evidence of sex‐related differences. The purpose of this study in Fischer 344 rats was to evaluate if there are sex‐related differences in DIAm sarcopenia, and if such differences translate to a functional impact on Pdi generation across motor behaviors and maximal Pdi (Pdimax) elicited by bilateral phrenic nerve stimulation. In both males and females, DIAm sarcopenia was apparent in 24‐month‐old rats with a ~30% reduction in both maximum specific force and the cross‐sectional area of type IIx and/or IIb fibers. Importantly, in both males and females, Pdi generated during ventilatory behaviors was unimpaired by sarcopenia, even during more forceful ventilatory efforts induced via airway occlusion. Although ventilatory behaviors were preserved with aging, there was a ~20% reduction in Pdimax, which likely impairs the ability of the DIAm to generate higher‐force expulsive airway clearance behaviors necessary to maintain airway patency.

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Section: Discussionmentioning

confidence: 99%

Impact of aging on diaphragm muscle function in male and female Fischer 344 rats

et al. 2018

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“…Previous studies suggest that DIAm sarcopenia is associated with a loss of motor neurons and fiber type‐selective atrophy (Greising, Mantilla, et al, ; Greising, Medina‐Martínez, et al, ; Khurram et al, ; Mantilla & Sieck, ), dysfunction at the neuromuscular junction (Fogarty, Gonzalez Porras, Mantilla, & Sieck, ; Greising, Stowe, Sieck, & Mantilla, ; Holter, Kierulf, & Refsum, ; Mantilla & Sieck, ), or intrinsic muscle changes including mitochondrial degeneration and autophagy (Gonzalez Porras, ). For instance, from 6 to 24 mo in C57BL/6 male and female mice, there is fiber type‐selective atrophy of large, high force generating type IIx and/or IIb fibers (Elliott, Omar, Mantilla, & Sieck, ; Greising, Mantilla, et al, , ; Greising, Medina‐Martínez, et al, ; Greising, Vasdev, Zhan, Sieck, & Mantilla, ). However, a recent study found significant DIAm hypertrophy of type IIx fibers (~30% increase in fiber cross‐sectional area (CSA)) in female CD‐1 mice at 20 mo compared to 5 mo (Messa et al, ).…”

Section: Introductionmentioning

confidence: 99%

Diaphragm muscle sarcopenia into very old age in mice

et al. 2020

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Sarcopenia is the age‐related decline of skeletal muscle mass and function. Diaphragm muscle (DIAm) sarcopenia may contribute to respiratory complications, a common cause of morbidity and mortality in the elderly. From 6 to 24 months (mo) of age, representing ~100% and ~80% survival in C57BL/6 × 129 male and female mice, there is a significant reduction in DIAm force generation (~30%) and cross‐sectional area (CSA) of type IIx and/or IIb muscle fibers (~30%), impacting the ability to perform high force, non‐ventilatory behaviors. To date, there is little information available regarding DIAm sarcopenia in very old age groups. The present study examined DIAm sarcopenia in C57BL/6 × 129 male and female mice at 24, 27, and 30 mo, representing ~80%, ~60%, and ~30% survival, respectively. We hypothesized that survival into older ages will show no further worsening of DIAm sarcopenia and functional impairment in 30 mo mice compared to 24 or 27 mo C57BL/6 × 129 mice. Measurements included resting ventilation, transdiaphragmatic pressure (Pdi) generation across a range of motor behaviors, muscle fiber CSA, and proportion of type‐identified DIAm fibers. Maximum Pdi and resting ventilation did not change into very old age (from 24 to 30 mo). Type IIx and/or IIb fiber CSA and proportions did not change into very old age. The results of the study support a critical threshold for the reduction in DIAm force and Pdi such that survival into very old age is not associated with evidence of progression of DIAm sarcopenia or impairment in ventilation.

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“…Larger motor unit potentials may generate larger forces that could be an adaptation to diaphragm muscle fibre atrophy (Greising et al . ), particularly in the stronger type II muscle fibre phenotype (Eddinger et al . ; Gosselin et al .…”

Section: Discussionmentioning

confidence: 99%

“…A larger action potential area in diaphragm motor units of middle-aged and older groups compared to the young group is consistent with age-related changes in the motor unit potentials observed in the genioglossus (Saboisky et al 2014) and vastus lateralis (Piasecki et al 2016) muscles. Larger motor unit potentials may generate larger forces that could be an adaptation to diaphragm muscle fibre atrophy (Greising et al 2017), particularly in the stronger type II muscle fibre phenotype (Eddinger et al 1985;Gosselin et al 1992;Prakash & Sieck, 1998;Imagita et al 2009;Greising et al 2013). A loss of type II fibres in humans is supported by the reduced maximal inspiratory muscle strength in the older participants.…”

Section: Motor Unit Potential Morphologymentioning

confidence: 99%

Discharge properties of human diaphragm motor units with ageing

Nguyen

Lewis

Gandevia

et al. 2019

The Journal of Physiology

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Key points Ageing is associated with changes in the respiratory system including in the lungs, rib cage and muscles. Neural drive to the diaphragm, the principal inspiratory muscle, has been reported to increase during quiet breathing with ageing. We demonstrated that low‐threshold motor units of the human diaphragm recruited during quiet breathing have similar discharge frequencies across age groups and shorter discharge times in older age. With ageing, motor unit action potential area increased. We propose that there are minimal functionally significant changes in the discharge properties of diaphragm motor units with ageing despite remodelling of the motor unit in the periphery. Abstract There are changes in the skeletal, pulmonary and respiratory neuromuscular systems with healthy ageing. During eupnoea, one study has shown relatively higher crural diaphragm electromyographic activity (EMG) in healthy older adults (>51 years) than in younger adults, but these measures may be affected by the normalisation process used. A more direct method to assess neural drive involves the measurement of discharge properties of motor units. Here, to assess age‐related changes in neural drive to the diaphragm during eupnoea, EMG was recorded from the costal diaphragm using a monopolar needle electrode in participants from three age groups (n ≥ 7 each): older (65–80 years); middle‐aged (43–55 years) and young (23–26 years). In each group, 154, 174 and 110 single motor units were discriminated, respectively. A mixed‐effects linear model showed no significant differences between age groups for onset (group mean range 9.5–10.2 Hz), peak (14.1–15.0 Hz) or offset (7.8–8.5 Hz) discharge frequencies during eupnoea. The motor unit recruitment was delayed in the older group (by ∼15% of inspiratory time; p = 0.02 cf. middle‐aged group) and had an earlier offset time (by ∼15% of inspiratory time; p = 0.04 cf. young group). However, the onset of multiunit activity was similar across groups, consistent with no global increase in neural drive to the diaphragm with ageing. The area of diaphragm motor unit potentials was ∼40% larger in the middle‐aged and older groups (P < 0.02), which indicates axonal sprouting and re‐innervation of muscle fibres associated with ageing, even in middle‐aged participants.

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Chronic TrkB agonist treatment in old age does not mitigate diaphragm neuromuscular dysfunction

Cited by 21 publications

References 59 publications

Impact of aging on diaphragm muscle function in male and female Fischer 344 rats

Impact of aging on diaphragm muscle function in male and female Fischer 344 rats

Diaphragm muscle sarcopenia into very old age in mice

Discharge properties of human diaphragm motor units with ageing

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