Mitochondrial Electron Transport Chain Function Is Enhanced in Inspiratory Muscles of Patients with Chronic Obstructive Pulmonary Disease

Abstract

In chronic obstructive pulmonary disease, inspiratory muscles face increased resistive and elastic workloads and therefore increased energy requirements. The adaptive response of these muscles to this higher energy demand includes increased oxidative enzymes and changes in contractile protein expression but the consequences on mitochondrial function and energy metabolism have not been assessed so far. We investigated the in situ properties of the mitochondria of costal diaphragm and external intercostal muscles using the skinned fiber technique in 9 emphysematous and 11 age-matched control patients. Biopsies obtained during thoracic surgery were placed in an oxygraphic chamber to measure maximal oxygen uptake. We observed that the maximal oxidative capacity of diaphragm and external intercostal muscles increased significantly in the emphysematous group compared with the control group (+135 and +37%, respectively). Significant correlations were found between the maximal oxidative capacity and patients' pulmonary indexes of obstruction (diaphragm: r = -0.637, intercostal: r = -0.667, p < 0.005) and hyperinflation (diaphragm: r = 0.639, p < 0.003, intercostal: r = 0.634, p < 0.01). Slow myosin heavy chain isoform increased in the diaphragm of the emphysematous group, with significant relationships between indexes of obstruction and hyperinflation and activities of biochemical mitochondrial markers. Thus, severe emphysema was associated with increased mitochondrial capacity and efficiency in the inspiratory muscles, supporting an endurance training-like effect.

Oxidised proteins and superoxide anion production in the diaphragm of severe COPD patients

“…In keeping with this, it has recently been proposed [23] that in severe COPD, several molecular mechanisms contribute to the aetiology of this respiratory muscle dysfunction, such as myosin loss [10,11], sarcomeric injury [24], oxidative stress [14] and alterations in cross-bridge cycling kinetics [8], resulting in reduced diaphragm isometric force. This raises serious questions concerning whether the adaptive mechanisms encountered in the diaphragms of severe COPD patients [4][5][6][7][8] are sufficient to make this muscle more efficient, since impaired contractile properties of the diaphragm muscle fibres have been clearly demonstrated [9][10][11].…”

“…Several reports have shown that in severe COPD the main inspiratory muscle, the diaphragm, undergoes adaptive modifications that probably render the overloaded muscle more resistant to fatigue [4][5][6][7][8]. However, there is growing evidence that in vitro fibre contractile function is also impaired in the diaphragms of patients with COPD [9], even at early stages of their disease, as shown by reduced myosin heavy chain (MyHC) content and increased protein degradation via the ubiquitin-proteasome pathway [10,11].…”

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

“…A parallel study by Wijnhoven et al (88) in a group of patients with largely moderate disease found increases in ␤-oxidation capacity and in mitochondrial respiratory enzyme activity that increased as a function of worsening disease severity. Parallel to the increases in oxidative enzyme capacity, diaphragm mitochondrial density, measured with electron microscopy, has been shown to increase in patients with COPD by an average of ϳ50% (59), and the mitochondrial oxidative capacity of permeabilized fibers increases as well (77). Both of these variables were also shown to increase as a function of disease severity (59,77).…”

“…Parallel to the increases in oxidative enzyme capacity, diaphragm mitochondrial density, measured with electron microscopy, has been shown to increase in patients with COPD by an average of ϳ50% (59), and the mitochondrial oxidative capacity of permeabilized fibers increases as well (77). Both of these variables were also shown to increase as a function of disease severity (59,77).…”

“…These results are complimented by analysis of MHC expression (Table 2). A general consensus finds a large increase in the MHC I isoform, corresponding to the myosin predominant in type I fibers (38,40,54,77) and relative decreases in MHC IIA (38) and IIX (38,77) isoforms. In addition, Nguyen et al (57) have shown that the proportion of fibers in the diaphragm that contain MHC I isoforms is significantly increased, whereas the proportion expressing IIA or IIB (probably IIX) isoforms is reduced.…”