There is substantial evidence that old age is associated with an increased incidence of respiratory complications that result from an inability to perform expulsive non-ventilatory behaviors such as coughing and sneezing. The proposed studies focus on the "perfect storm" condition related to old age, where we believe that sarcopenia (diaphragm muscle (DIAm) fiber atrophy and decreased specific force) together with increased neuromuscular transmission failure reduce the ability of the DIAm to generate force, and thus transdiaphragmatic pressure (Pdi), while at the same time the respiratory system mechanics are stiffening thereby increasing the load against which the DIAm must contract. The DIAm must accomplish a range of behaviors from resting breathing to expulsive behaviors such as coughing and sneezing. In the elderly, a deficit in the ability to perform expulsive, high-intensity, non-ventilatory behaviors likely contributes to increased risk for infections and respiratory failure. Our working hypothesis is that age-related sarcopenia and neuromuscular transmission failure reduce maximum DIAm force-generating capacity, impairing the ability of the elderly to perform non-ventilatory behaviors involved in airway clearance. The proposed research will determine the role of trophic influences exerted by brain-derived neurotrophic factor (BDNF) acting through tropomyosin related kinase receptor (TrkB) and neuregulin-1 (NRG-1) acting through ErbB receptors via mTOR activation on the age-related changes in DIAm innervation and sarcopenia. We hypothesize that trophic influences exerted by BDNF/TrkB and NRG-1/ErbB/mTOR signaling can be used therapeutically to mitigate aging-related DIAm neuromuscular transmission failure and sarcopenia, and the associated impairment of non-ventilatory behaviors. We propose the following three specific aims to address these hypotheses: 1) To determine the functional impact of old age on respiratory mechanics;2) To determine the role of BDNF/TrkB signaling on the age-related changes in DIAm innervation;and 3) To determine the role of NRG-1/ErbB/mTOR signaling in age- related DIAm sarcopenia. The results of the proposed studies will provide new and fundamental knowledge of changes in the respiratory system in old age, and thus permit the development of novel therapies with broad application in respiratory and neuromuscular diseases. The greater incidence of chronic diseases associated with the aging of our population demands concerted efforts to improve the wellness of the elderly.

Public Health Relevance

The number of elderly individuals in the United States is expected to increase markedly to more than 70 million by 2030, and with this demographic change there will be an increased incidence of respiratory complications that result from an inability to perform expulsive non-ventilatory behaviors such as coughing and sneezing. The proposed studies focus on the perfect storm condition related to old age, where diaphragm muscle (DIAm) fiber atrophy, decreased force and neuromuscular transmission failure reduce the ability of the DIAm to generate force, while at the same time the respiratory system mechanics are stiffening thereby increasing the load against which the DIAm must contract. The proposed studies will provide important information regarding the potential therapeutic role of trophic factors in the age-related decline in respiratory function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG044615-02
Application #
8665855
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Murthy, Mahadev
Project Start
2013-06-01
Project End
2018-04-30
Budget Start
2014-06-15
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
$414,788
Indirect Cost
$150,872
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Elliott, Jonathan E; Omar, Tanya S; Mantilla, Carlos B et al. (2016) Diaphragm muscle sarcopenia in Fischer 344 and Brown Norway rats. Exp Physiol 101:883-94
Elliott, Jonathan E; Greising, Sarah M; Mantilla, Carlos B et al. (2016) Functional impact of sarcopenia in respiratory muscles. Respir Physiol Neurobiol 226:137-46
Greising, Sarah M; Stowe, Jessica M; Sieck, Gary C et al. (2015) Role of TrkB kinase activity in aging diaphragm neuromuscular junctions. Exp Gerontol 72:184-91
Greising, Sarah M; Ermilov, Leonid G; Sieck, Gary C et al. (2015) Ageing and neurotrophic signalling effects on diaphragm neuromuscular function. J Physiol 593:431-40
Greising, Sarah M; Medina-Martínez, Juan S; Vasdev, Amrit K et al. (2015) Analysis of muscle fiber clustering in the diaphragm muscle of sarcopenic mice. Muscle Nerve 52:76-82
Medina-Martínez, Juan S; Greising, Sarah M; Sieck, Gary C et al. (2015) Semi-automated assessment of transdiaphragmatic pressure variability across motor behaviors. Respir Physiol Neurobiol 215:73-81
Gill, Luther C; Mantilla, Carlos B; Sieck, Gary C (2015) Impact of unilateral denervation on transdiaphragmatic pressure. Respir Physiol Neurobiol 210:14-21
Greising, Sarah M; Mantilla, Carlos B; Medina-Martínez, Juan S et al. (2015) Functional impact of diaphragm muscle sarcopenia in both male and female mice. Am J Physiol Lung Cell Mol Physiol 309:L46-52
Mantilla, Carlos B; Seven, Yasin B; Sieck, Gary C (2014) Convergence of pattern generator outputs on a common mechanism of diaphragm motor unit recruitment. Prog Brain Res 209:309-29
Mantilla, Carlos B; Stowe, Jessica M; Sieck, Dylan C et al. (2014) TrkB kinase activity maintains synaptic function and structural integrity at adult neuromuscular junctions. J Appl Physiol (1985) 117:910-20

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