Aging, Neuromuscular Disease and Increased Risk of Respiratory Complications

The greater incidence of chronic diseases associated with aging populations demands concerted efforts to improve wellness in older adults.

In this research project, Dr. Mantilla is exploring mechanisms underlying respiratory muscle weakness in a variety of conditions and situations. These include aging, prolonged mechanical ventilation and neuromuscular diseases such as amyotrophic lateral sclerosis (ALS). The ultimate goal is to improve function and prevent complications in patients with respiratory muscle weakness.

Our project focuses on the perfect storm of conditions where muscle fiber atrophy combines with decreased force and neuromuscular transmission failure. This combination reduces the ability of respiratory muscles to generate adequate forces to sustain ventilation and keep airways clear. Our research is aimed at understanding the potential therapeutic role of trophic factors in mitigating the age-related decline in respiratory function. We're studying the impact of different families of growth factors, such as neurotrophins and neuregulins, in regulating neuromuscular transmission, muscle fiber properties and motor neuron survival.

Respiratory control in older age

Substantial evidence shows that older age is associated with an increased incidence of respiratory complications. These complications result from an inability to perform expulsive nonventilatory behaviors, such as coughing and sneezing.

Our working hypothesis is that age-related muscle atrophy, also called sarcopenia, and neuromuscular transmission failure reduce maximum diaphragm muscle force-generating capacity. This impairs the ability of older adults to perform nonventilatory behaviors involved in airway clearance, which increases the risk of respiratory complications.

The project focuses on the age-related condition in which sarcopenia in the diaphragm decreases the specific force the muscle is able to exert. The effects of this atrophy are combined with increased neuromuscular transmission failure, which further reduces the diaphragm's ability to generate force and thus transdiaphragmatic pressure. At the same time, the respiratory system mechanics gradually stiffen, thereby increasing the load against which the diaphragm muscle must contract.

The diaphragm muscle must accomplish a range of behaviors, from resting breathing to expulsive behaviors such as coughing and sneezing. In older adults, a deficit in the ability to perform expulsive, high-intensity, nonventilatory behaviors likely contributes to the increased risk of infections and respiratory failure.

We're studying how two things affect age-related changes in diaphragm muscle innervation and sarcopenia: The role of trophic influences exerted by brain-derived neurotrophic factor (BDNF) acting through tropomyosin related kinase receptor (TrkB), and the role of neuregulin-1 (NRG-1) acting through ErbB receptors via mTOR activation.

Dr. Mantilla hypothesizes that trophic influences exerted by BDNF-TrkB and NRG-1-ErbB-mTOR signaling can be used therapeutically to mitigate aging-related diaphragm muscle neuromuscular transmission failure and sarcopenia along with the associated impairment of nonventilatory behaviors.

We're addressing this hypothesis through three specific aims:

  • Determining the functional impact of older age on respiratory mechanics.
  • Determining the role of BDNF-TrkB signaling on age-related changes in diaphragm muscle innervation.
  • Determining the role of NRG-1-ErbB-mTOR signaling in age-related diaphragm muscle sarcopenia.

The results of this research project will provide new and fundamental knowledge about changes in the respiratory system in older age. This may lead to developing novel therapies with broad application in respiratory and neuromuscular diseases.