The major limitation to exercise performance in COPD is inadequate energy supply to the respiratory and locomotor muscles

POINT-COUNTERPOINTThe major limitation to exercise performance in COPD is inadequate energy supply to the respiratory and locomotor musclesAndrea Aliverti, and Peter T. MacklemAndrea Aliverti, and Peter T. MacklemPublished Online:01 Aug 2008https://doi.org/10.1152/japplphysiol.90336.2008This is the final version - click for previous versionMoreSectionsPDF (139 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations No doubt dynamic hyperinflation and lack of oxidative capacity of skeletal muscles are important causes of exercise limitation in COPD. O'Donnell and Webb and Debigaré and Maltais will convince the reader of this by the elegant experiments they have performed. The thesis we will put forward is that during the natural history of COPD the primary factors leading to impairment of exercise performance are an increase in energy demands combined with a decrease in supplies and that both of these result from excessive recruitment of expiratory muscles. We argue that both dynamic hyperinflation and reduced oxidative capacity are secondary adaptations resulting from this primary abnormality.Increased energy demands during exercise in COPD.Energy demands are increased in COPD because of the high O2 cost of breathing (V̇o2resp). In health, V̇o2resp is only 1–3 ml O2/l breathed, whereas in COPD it has been reported variously to average 6.3, 9.7, and 16.4 ml/l breathed with individual values ranging from 3.0 to 19.5 ml/l (8, 17).The large between patient range in V̇o2resp probably reflects variation in the work of breathing (Wresp). During exercise, a large variation in Wresp certainly exists. In two studies, COPD patients formed two distinct groups: those that strongly recruited abdominal muscles and those that did not (5, 10). In the first (5), at an exercise workload of 10 W the work performed on the lung averaged 754 cmH2O·l−1·min−1 in recruiters but only 277 cmH2O·l−1·min−1 in nonrecruiters, although ventilation was similar. Expiratory muscle activation is the normal response to exercise (1) so the recruiters behaved normally. The problem is that in COPD, it fails to increase ventilation, because expiratory flow becomes limited by high pleural pressures. While abdominal muscle recruitment is beneficial during exercise in health (1), it is definitely harmful in COPD (4, 5).Because Wresp was 2.7-fold greater in recruiters, we can assume that their V̇o2resp was twice as high as the nonrecruiters. Let's also assume that it was 12 ml O2/l in the former and 6 ml/l in the latter. The maximal exercise workload (Wmax) was 20 and 35 W in recruiters and nonrecruiters (P < 0.05), while V̇e at Wmax was 35.9 and 37.9 l/min, respectively (5). Thus the estimated V̇o2resp was 430.8 ml/min in recruiters but only 227.4 ml/min in nonrecruiters. From the measured values of V̇o2 at rest and during 10 W exercise and assuming that V̇o2 increased linearly (dV̇o2/dwatt is constant) the V̇o2 at maximal exercise workload (V̇o2max) was 830.0 and 1,327.5 ml O2/min, respectively, in recruiters and nonrecruiters. Subtracting V̇o2resp from V̇o2max reveals that if the respiratory muscles received all their demands there was only 399.2 ml O2 available to locomotor muscles and other body tissues in recruiters but 1,100.1 ml in nonrecruiters. The respiratory muscles demanded 53% of V̇o2max in recruiters but only 17%, a value close to normal (6), in nonrecruiters.The nonrecruiters' breathing pattern was abnormal because abdominal muscles were not recruited during exercise. As a result, their exercise performance was better. However, their resting lung function was worse. Both the FEV1 and FEV1/FVC were significantly lower in nonrecruiters. This strongly suggests that as COPD progresses, patients eventually realize that abdominal muscles recruitment is bad and somehow they learn to derecruit them. Alas, without abdominal muscle contraction they dynamically hyperinflate. They can exercise a bit more, but not much (15). Thus we believe that dynamic hyperinflation results from a learned response to an inadequate supply of energy to meet demands.Decreased energy supplies during exercise with expiratory flow limitation.When normal subjects breathe with a Starling resistor in the expiratory line, which limits expiratory flow to ∼1 l/s, exercise is limited by severe dyspnea; abdominal pressure (Pab) increases abnormally; duty cycle decreases; CO2 retention occurs, increasing Pab even more (3, 13, 14); the high expiratory pressures and short duty cycle act like a Valsalva maneuver and decrease cardiac output (Q′c) (2); as a result, O2 debt is increased by 52% (22). Expiratory flow limitation (EFL) decreases the shortening velocity of abdominal muscles, and, in accordance with their force velocity characteristics Pab increases (3). Expiratory muscle recruitment can account for 66% of the variation in Borg scale ratings of difficulty in breathing (14). None of these abnormalities can be attributed to either dynamic hyperinflation or impaired oxidative capacity of skeletal muscles.Does this scenario occur in COPD? There is strong evidence that it does. First, there is uniform agreement that lactic acid production occurs at a very low exercise level in COPD. This suggests an imbalance between energy supply and demand, resulting in competition between respiratory and locomotor muscles for limited energy supplies (9, 12, 20). Administration of O2 improves exercise performance probably by decreasing V̇o2resp (7), thereby releasing more energy for locomotor muscles. This improvement should not occur if skeletal muscles were unable to use the energy available to them. Richardson et al. (19) showed that in small muscle mass exercise in COPD there was a 2.2-fold greater mass-specific power output than during whole body exercise. Locomotor muscles have a greater maximal power output in the absence of respiratory-locomotor muscle competition, Oelberg et al. (18) reported a Q′c of only 39% of predicted during exercise in COPD and when heliox was breathed, decreasing V̇o2resp and increasing the energy available to locomotor muscles, V̇o2 increased by 15% without any change in Q′c (18). If the respiratory muscles in recruiters demand 53% of V̇o2max, they probably demand the same share of Q′c (6), and if Q′c is only 39% predicted, locomotor muscles must be pretty ischemic. Finally Francois (21) himself reported a plateau in lower limb perfusion while exercise workload increased in COPD.If inadequate energy to meet demands limits exercise in COPD, why is the oxidative capacity of skeletal muscles reduced? The obvious answer is that disuse and lack of energy supplies (tissue hypoxia) cause the enzymatic changes and mitochondrial abnormalities responsible for decreasing oxidative capacity. Again there is strong evidence that this is so [see Gosker et al. (11) for an outstanding review]. The myopathic changes in congestive heart failure and COPD are almost identical. They do not occur in the diaphragm because there is no disuse of this muscle. There is no reason to believe that myopathy is a primary abnormality in COPD and congestive heart failure and every reason to believe that it is secondary to disuse and tissue hypoxia. Francois refers to this when he states "…a comparable disorder has been described in chronic heart failure. Chronic reduction in oxygen availability at the cellular level…could contribute to…skeletal muscle dysfunction" (16). Francois also recognized the potential importance of respiratory-locomotor muscle competition when he wrote that in COPD "…the respiratory muscles, with [high] V̇o2 during exercise…might…compete with lower limb muscles for the available blood flow and O2" (21). Yes, reduced oxidative capacity, like dynamic hyperinflation, can limit exercise performance in COPD, but it is secondary to a longstanding imbalance between energy supply and demand.We believe the long natural history of COPD results in the sequence of events during exercise shown in Fig. 1. The primary event, EFL during exercise, probably occurs when the disease is still mild and exercise is not seriously impaired. This in turn leads to an increase in force generation of expiratory muscles increasing expiratory pressures from which all the pathophysiology described above derives.Fig. 1.Natural history of COPD and its results in the sequence of events during exercise.Download figureDownload PowerPointREFERENCES1 Aliverti A, Cala SJ, Duranti R, Ferrigno G, Kenyon CM, Pedotti A, Scano G, Sliwinski P, Macklem PT, Yan S. Human respiratory muscle actions and control during exercise. J Appl Physiol 83: 1256–1269, 1997.Link | ISI | Google Scholar2 Aliverti A, Dellaca RL, Lotti P, Bertini S, Duranti R, Scano G, Heyman J, Lo MA, Pedotti A, Macklem PT. Influence of expiratory flow-limitation during exercise on systemic oxygen delivery in humans. Eur J Appl Physiol 95: 229–242, 2005.Crossref | ISI | Google Scholar3 Aliverti A, Iandelli I, Duranti R, Cala SJ, Kayser B, Kelly S, Misuri G, Pedotti A, Scano G, Sliwinski P, Yan S, Macklem PT. 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