DIAPHRAGM ADAPTATIONS TO CHRONIC RESISTIVE LOADING

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?