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- chronic obstructive pulmonary disease
- lipid peroxidation
- oxidised protein
New findings on the biological defects underlying oxidative damage in patients with COPD
Chronic bronchitis and pulmonary emphysema, also know as chronic obstructive pulmonary disease (COPD), is the only leading cause of death with a rising prevalence.1 Typically, the reduced lung function of COPD patients is associated with a general deconditioning of muscle function and the consequent development of a sedentary lifestyle.2 There is clear evidence that pulmonary rehabilitation programmes that involve generic physical exercise training can improve exercise capacity and state of health in patients with COPD,3 so outpatient and home based exercise training are part of the rehabilitation programme for these subjects in Western countries.4
The role of co-factors such as hypoxia and inflammation on the health of COPD patients and the resulting improvements of exercise performance with training are poorly understood, but the paper by Koechlin and colleagues5 in this issue of Thorax shows that exercise performance and peripheral muscle defects in patients with COPD relate to the level of arterial oxygenation. Using biochemical measures, the authors found that COPD patients with hypoxaemia had higher basal and resistance exercise induced levels of oxidatively damaged lipids and proteins in the vastus lateralis muscle than non-hypoxaemic patients. At baseline, the muscles of hypoxaemic COPD patients also had more lipofuscin inclusions in the muscle fibres and higher neutrophil numbers in the quadriceps muscle. These results suggest that adequate muscle oxygenation is critical to preventing the accumulation of wasteful oxidised lipid products and the harmful downstream reactions that are potentially associated with muscle wasting.6–8 Correlation analysis of endurance and arterial oxygen pressure in COPD patients also suggested that blood oxygenation might predict muscle (dys)function. These observations provide an important insight into the biological defects underlying oxidative damage in patients with COPD. The findings may be of relevance for optimising rehabilitation programmes to overcome muscle damage and exercise intolerance, thereby helping to maximise peripheral components of the syndrome.
MUSCLE OXYGEN TENSION AND LIPID OXIDATION
It has long been known from studies on high altitude dwellers that there may be an intimate relationship between oxygenation, muscle performance, and oxidative stress.9 The study performed by Koechlin et al5 using molecular probes now carries these observations to a clinically relevant level. Similar to the accumulation of lipofuscin in the muscles of hypoxaemic COPD patients, increased amounts of this lipid degradation product can be found in muscle cells of mountaineers returning from the Himalayas.9,10 This suggests that there is a close relationship between reduced muscular oxygen tension and the accumulation of lipid products in hypoxaemic COPD patients. The unbuffered formation of oxygen radicals with myocellular respiration11 is the likely origin of the oxidative damage of lipids with exercise. The production of reactive oxygen species (ROS) is a byproduct of mitochondrial electron transport during increased mitochondrial respiration.9,12 In hypoxia it can be exaggerated due to increased mitochondrial oxygen consumption resulting from an inequality of oxygen flow and electron transport in the mitochondrial respiratory chain. Heavy exhaustive types of exercise are known to increase lipid peroxidation in the skeletal muscle of healthy subjects.13,14 The formation of ROS is thus seen as a regular response of skeletal muscle to increased contractile activity and constitutes an important part of the adaptive signal.15–17 Under “physiologically normal” conditions, these ROS are buffered by several antioxidant systems in order to prevent oxidative damage of mitochondrial lipids and lipofuscin accumulation (fig 1).9,10 The study by Koechlin et al now shows that, in hypoxaemic COPD patients, there is an important mismatch in the radical scavenging and redox forces that fails to prevent the damage associated with the increase in ROS during enhanced mitochondrial electron flux. In conjunction with the previous observation that patients with COPD have enhanced lipofuscin accumulation in the vastus lateralis muscle, this suggests a progressive relationship between arterial oxygenation and oxidative muscle damage.18
There is evidence that the antioxidant capacity of skeletal muscles in hypoxaemic COPD patients is insufficient to cope with the increasing production of reactive oxygen radicals during exercise at low muscular oxygen tension. For instance, the skeletal muscle fibres of patients with COPD are known to undergo transformation towards a poorly oxygenated type.19,20 In addition, it has recently been shown that the total antioxidant capacity of skeletal muscle is markedly higher in patients with COPD than in healthy controls.21 Intriguingly, the selective augmentation of glutathione-S-transferase activity in the muscles of patients with COPD21 resembles the permanent augmentation of the P1-1 glutathione-S-transferase isoform in high altitude residents who are protected from lipofuscin accumulation.22 An understanding of the protective radical scavenging mechanisms is important as ROS formation and inflammation are related to muscle wasting, a common feature of patients with COPD.6,19
EXERCISE AS A REMEDY FOR COPD
These findings on mitochondrial damage in hypoxaemic COPD patients raise questions as to whether the detrimental effects can be overcome by adaptive changes with endurance training. There is reason to believe that repetition of the endurance training stimulus will improve the protective components that reduce the accumulation of oxidative damaged lipids and proteins, the lipofuscin end product of which appears undegradable (fig 1).10 For instance, a single bout of exhaustive exercise is known to improve the defence system involved in the scavenging of ROS and possible lipidic mitochondrial targets and DNA repair enzymes within days after recovery from exercise.7,23,24 With repetition of the exercise stimulus, a permanent increase in antioxidant activity as well as an improvement in capillary and mitochondrial density are evident in actively recruited muscle.25–29 Regular exercise therefore provides an important signal leading to improved oxidative stress defence in skeletal muscle.15–17 Importantly, exercise training for 3–6 months in patients with chronic heart failure is known to enhance the antioxidant capacity in skeletal muscle via an increase in the activity and gene expression of the radical scavenger enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD).28,30,31 These patients experience significant muscular dysfunction which is similar to that in patients with COPD. The protective effect of exercise on the heart from myocardial ischemia-reperfusion injury is well known.32 In the study by Koechlin et al5 there was no statistically significant increase in GPx and SOD activity 2 days after exercise. In conjunction with previous observations,24 this suggests that more intense or repetitive training sessions rather than a single bout of exercise are needed to increase the concentration of radical scavenging systems.
Clearly, more research is needed to resolve which exercise training strategy is more suitable for improving the exercise capacity of COPD patients, in view of limited antioxidant defence in the chronically deconditioned locomotory muscles. Studies are needed to determine whether the initial overshoot of oxidative damage in the untrained state should be minimised. These studies should also examine whether moderate training stimuli and supplementation with certain antioxidant nutrients may be better than heavier types of exercise which produce considerably more ROS.13,31 Occasional resistance exercise may be an alternative to plain endurance types of exercise. The former kind of training is known to improve other aspects of muscle dysfunction such as mechanical efficiency,33 while possibly preserving capillarity.34
The study by Koechlin and co-workers provides important findings on muscular limitations in the hypoxaemic subpopulation of COPD patients, which are of relevance for optimal exercise recommendations. The results indicate that the amount and kind of physical activity in this exercise intolerant subpopulation2 need to be finely tuned to avoid possible adverse initial muscular defects, and suggest that personalised therapeutic approaches are needed to treat peripheral muscle dysfunction in patients with COPD.
New findings on the biological defects underlying oxidative damage in patients with COPD