Respiratory muscle fiber remodeling in chronic hyperinflation: dysfunction or adaptation?

Abstract

The diaphragm and other respiratory muscles undergo extensive remodeling in both animal models of emphysema and in human chronic obstructive pulmonary disease, but the nature of the remodeling is different in many respects. One common feature is a shift toward improved endurance characteristics and increased oxidative capacity. Furthermore, both animals and humans respond to chronic hyperinflation by diaphragm shortening. Although in rodent models this clearly arises by deletion of sarcomeres in series, the mechanism has not been proven conclusively in human chronic obstructive pulmonary disease. Unique characteristics of the adaptation in human diaphragms include shifts to more predominant slow, type I fibers, expressing slower myosin heavy chain isoforms, and type I and type II fiber atrophy. Although some laboratories report reductions in specific force, this may be accounted for by decreases in myosin heavy chain content as the muscles become more oxidative and more efficient. More recent findings have reported reductions in Ca(2+) sensitivity and reduced myofibrillar elastic recoil. In contrast, in rodent models of disease, there is no consistent evidence for loss of specific force, no consistent shift in fiber populations, and atrophy is predominantly seen only in fast, type IIX fibers. This review challenges the hypothesis that the adaptations in human diaphragm represent a form of dysfunction, secondary to systemic disease, and suggest that most findings can as well be attributed to adaptive processes of a complex muscle responding to unique alterations in its working environment.

Fig. 1.

Effects of chronic hyperinflation on diaphragm muscle length-force relationships in animals (A and B) and humans (C and D). A: dramatic shortening of hamster diaphragm fiber length with chronic adaptation to elastase emphysema. B: data from A, when diaphragm force is expressed as function of sarcomere length. Sarcomere length remains essentially constant following adaptation. C: effects of lung volume and hyperinflation on maximum transdiaphragmatic force (Pdi_max) development in emphysema patients and controls. Residual volume (RV) in the patient group was 288% predicted. D: Pdi_max, as in C, expressed as a function of diaphragm length, normalized to patient height [diaphragm length index (DLI)]. Data demonstrate that, at FRC, diaphragm length is substantially shorter in emphysema compared with controls and can generate significant elevations in pressure at that specific length. FRC, functional residual capacity; TLC, total lung capacity. [A and B, reproduced from Supinski and Kelsen (85) with permission from American Society for Clinical Investigation; C and D, adapted from Bellemare et al. (3) with permission.]

Fig. 2.

Diaphragm fiber type and size adaptations. A: diaphragm fibers stained for myosin ATPase for fiber typing in a control diaphragm. B: fiber-type staining of a diaphragm from a patient with severe emphysema showing typical increases in type I fiber populations, atrophy of type I fibers, and reduction in type IIax numbers. C: the relationship between the severity of hyperinflation and the shift in the proportion of type I fibers. The two linear regressions represent controls (left; dotted line) and hyperinflated chronic obstructive pulmonary disease patients (right; dashed line). D: changes in the area fraction, i.e., the proportion of the total cross-sectional area of the diaphragm taken up by type I fibers, as a function of increasing hyperinflation. Symbols and lines are as defined in C. [A and B, reproduced from Levine et al. (37); C and D, reproduced from Levine et al. (40) with permission from American Thoracic Society.]

Fig. 3.

A: restoring force (a measure of passive elastic properties) of single fibers from biopsy specimens of human diaphragm in normal subjects (▪) and patients with moderate hyperinflation (□). B: schematic of the relationship of the macromolecule titin and the extracellular elastic matrix, both of which contribute to the parallel elastic elements of the intact muscle. Alterations in extracellular matrix elasticity could be compensated for by alterations in titin splice variant expression. [A, reproduced from Moore et al. (55).]