Aging, Neuromuscular Disease and Increased Risk of Respiratory Complications Program

The Regenerative Physiology Laboratory's Aging, Neuromuscular Disease and Increased Risk of Respiratory Complications Program explores the mechanisms underlying muscle weakness in a variety of conditions, including aging, neuromuscular diseases — such as amyotrophic lateral sclerosis (ALS) — and prolonged mechanical ventilation.

The program focuses on the perfect storm conditions where muscle fiber atrophy and decreased force and neuromuscular transmission failure reduce the ability of respiratory muscles to generate adequate forces to sustain ventilation and keep airways clear. Research is aimed at understanding the potential therapeutic role of trophic factors in mitigating the age-related decline in respiratory function.

The Regenerative Physiology Lab is examining the impact of different families of growth factors (neurotrophins and neuregulins) in the regulation of neuromuscular transmission, muscle fiber properties and motor neuron survival in order to improve function and prevent complications in patients with respiratory muscle weakness.

Current research: Respiratory Control in Old Age Project

There is substantial evidence that old age is associated with an increased incidence of respiratory complications that result from an inability to perform expulsive nonventilatory behaviors such as coughing and sneezing.

The lab's working hypothesis in the Respiratory Control in Old Age Project is that age-related muscle atrophy (sarcopenia and neuromuscular transmission failure reduce maximum diaphragm muscle force-generating capacity, impairing older adults' abilities to perform nonventilatory behaviors involved in airway clearance and thereby increasing their risks of respiratory complications.

The project focuses on the age-related condition wherein 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 are gradually stiffening, 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 increased risk of infections and respiratory failure.

The Respiratory Control in Old Age Project is aimed at determining 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 diaphragm muscle innervation and sarcopenia.

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, and the associated impairment of nonventilatory behaviors.

This research project addresses this hypothesis via the following three specific aims:

  • Determining the functional impact of old age on respiratory mechanics
  • Determining the role of BDNF-TrkB signaling on the 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 the Respiratory Control in Old Age Project 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 aging populations demands concerted efforts to improve the wellness of older adults.

Sarah M. Greising, Ph.D., collaborates on this research.