Project: Research project

Project Details


DESCRIPTION (Applicant's abstract): Long-term goal: In patients with
chronic obstructive pulmonary diseases (COPD), respiratory muscle fatigue
resistance must be increased to maintain ventilation in the face of chronic
respiratory resistive loading (CRRL). Unfortunately, respiratory muscle
strength is often not adequate to meet acute increases in resistive workload
that occurs during clinical exacerbations. Our efforts are to understand
the mechanisms by which the diaphragm adapts to CRRL and to provide a basis
for a scientific approach to prevention and reversal of respiratory muscle
dysfunction in COPD patients who require ventilatory support or whose
spontaneous ventilatory capacity is insufficient for daily activities.
Hypothesis 1: Given adequate blood flow, 2 factors important for fatigue
resistance are: a) economy of ATP turnover, determined largely by myosin
heavy chain (MHC) isoform composition, and b) mitochondrial oxidative
phosphorylation capacity. This grant focuses on how these 2 factors are
altered as the diaphragm adapts to CRRL. Using a model of long-term (6 mo)
CRRL, we found the diaphragm, a mixed fiber type muscle and the principal
inspiratory muscle, adapts by increasing number and cross-sectional area of
type I, fatigue resistant fibers. I propose that shifts in MHC isoforms and
thus fiber types are responsible for creating a performance
paradox--increased fatigue resistance but decreased specific force.
Specific aim 1: Determine effect of CRRL on diaphragm structure and MHC
gene expression. Hypothesis 2: Increased fatigue resistance also requires
a mechanism by which diaphragm mitochondrial oxidative phosphorylation is
linked to cytosolic energy demands so that a steady state is maintained. In
this same long-term CRRL model, we found an increase in diaphragm
mitochondrial oxidative phosphorylation (state 3 resp.) capacity. I propose
that the diaphragm adapts to CRRL with work related changes in mitochondrial
oxidative phosphorylation capacity and that the primary control point is the
enzyme ATP synthase. Specific aim 2: Determine the effect of CRRL on the
control of diaphragm mitochondrial oxidative phosphorylation. Hypothesis 3:
In COPD patients, adaptations leading to increased fatigue resistance remain
favorable as long as strength exceeds demand. However, when the resistive
load acutely increases during clinical exacerbations, strength is no longer
adequate and ventilatory failure may ensue. I propose that respiratory
muscle dysfunction in COPD patients results primarily from this
(mal)adaptation. Specific aim 3: Determine effects of an acute increase in
respiratory resistive load on the structure and function of diaphragm muscle
already adapted to CRRL. Do prior adaptations make the diaphragm more or
less susceptible to exercise-induced muscle injury?
Effective start/end date8/1/976/30/02


  • Pulmonary and Respiratory Medicine


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