Skeletal muscle dysfunction in chronic obstructive pulmonary disease
Respiratory Research volume 2, Article number: 216 (2001)
It has become increasingly recognized that skeletal muscle dysfunction is common in patients with chronic obstructive pulmonary disease (COPD). Muscle strength and endurance are decreased, whereas muscle fatigability is increased. There is a reduced proportion of type I fibers and an increase in type II fibers. Muscle atrophy occurs with a reduction in fiber cross-sectional area. Oxidative enzyme activity is decreased, and measurement of muscle bioenergetics during exercise reveals a reduced aerobic capacity. Deconditioning is probably very important mechanistically. Other mechanisms that may be of varying importance in individual patients include chronic hypercapnia and/or hypoxia, nutritional depletion, steroid usage, and oxidative stress. Potential therapies include exercise training, oxygen supplementation, nutritional repletion, and administration of anabolic hormones.
COPD is a chronic debilitating disease with disabling symptoms. Our ability to improve lung function pharmacologically in patients with COPD is quite limited. Surgical options (lung volume reduction surgery, lung transplantation) can produce substantial improvements in some patients, but are associated with significant morbidity and mortality, and are only indicated in a minority of patients. It has recently become apparent that skeletal muscle dysfunction is common in patients with COPD, and may play a role in reducing exercise tolerance. Therapeutic efforts to improve skeletal muscle function could lead to considerable benefits in such patients. The present review focuses on the evidence for skeletal muscle dysfunction in patients with COPD, as well as on potential mechanisms of and therapies to combat this dysfunction.
Skeletal muscle dysfunction
Muscle strength is decreased in patients with COPD as compared with age-matched control individuals [1,2,3]. Lower limb muscles are affected to a greater extent than are upper limb muscles [1,2,3]. The preferential reduction in lower limb strength may be due to a greater reduction in activity of the lower limbs in these patients. On average, quadriceps strength is decreased by 20–30% in patients with moderate to severe COPD [2,3]. However, there is considerable variability among patients, with some patients having relatively normal values, whereas others have a reduction in strength of more than 50%.
In one study , the cross-sectional area of the thigh was measured using computed tomography scanning. In that study the reduction in strength was proportional to the reduction in thigh area (ie the reduction in strength was entirely due to muscle atrophy). A subgroup of patients who had previously received steroids did have a greater reduction in strength than in muscle mass. Further studies are required to determine whether patients with particular clinical characteristics will display a reduction in muscle strength that is out of proportion to their reduction in muscle mass. Quadriceps strength was significantly correlated with the forced expiratory volume in 1 s (FEV1) ; the lower the FEV1, the weaker the quadriceps muscle. Quadriceps strength also correlated with exercise capacity, both peak exercise capacity [1,3] and 6-min walking distance , independently of lung function. However, correlation does not represent causation.
Several studies [4,5,6] have compared limb muscle endurance in patients with COPD and healthy control individuals. Measurement of endurance is particularly affected by motivational factors, and variability in measurements can be quite high. Two studies [4,5] examined quadriceps endurance. One study found a significant reduction in quadriceps endurance in patients with COPD , whereas the other did not . This finding may reflect heterogeneity in skeletal muscle function between patients with COPD. However, the smaller number of patients evaluated in the negative study (six versus 17) may also be important. Small reductions in endurance of upper limb muscles (elbow flexors and adductor pollicis) have also been demonstrated in patients with COPD [5,6].
When normal individuals exercise vigorously the exercising muscle develops contractile fatigue. With contractile fatigue, the force generated by the muscle for a given neural input decreases. Patients with COPD become breathless when they exercise, and may stop exercise because of breathlessness before they stress the exercising musclesufficiently to develop fatigue.
We measured quadriceps twitch force (a measure of fatigue) before and after high-intensity cycle exercise to the limits of tolerance in a group of patients with moderately severe COPD . We found a significant reduction in twitch force after exercise in 11 out of 19 patients. Thus, the majority of patients displayed contractile fatigue of the quadriceps muscle (the primary working muscle during stationary cycling) despite their having a severely reduced exercise capacity (the peak oxygen consumption [VO2] averaged 51% of predicted). In a subsequent study we measured potentiated quadriceps twitch force (a more sensitive index of contractile fatigue ) in a group of patients with COPD of varying severity. Potentiated twitch force fell in 17 out of 21 patients after exercise . Thus, most patients with COPD will develop contractile fatigue of the exercising muscle after exercise to the limits of tolerance. Patients with severe disease (FEV1 <40% of predicted) were as likely to develop exercise-induced quadriceps fatigue (seven out of nine) as those with milder disease (10 out of 12) .
Healthy elderly individuals also develop exercise-induced quadriceps fatigue after cycle exercise to the limits of tolerance . The degree of exercise-induced quadriceps fatigue was not significantly different between the healthy elderly and the patients with COPD, even though the patients with COPD exercised at a significantly lower workload. These results suggest that the quadriceps muscle is more fatigable in patients with COPD than in healthy elderly persons.
Muscle fiber type
In general, biopsies of the quadriceps muscle in patients with COPD have shown a reduced proportion of type I fibers and an increase in the proportion of type II fibers as compared with normal individuals [11,12,13,14,15]. Type I fibers are slow-twitch fibers, develop a relatively small tension, have increased oxidative capacity, and are resistant to fatigue. Type IIb fibers are fast-twitch fibers, develop high tensions, depend primarily on anaerobic glycolytic metabolism, and are highly susceptible to fatigue. Type IIa fibers are intermediate in character. The increased proportion of type II fibers was of type IIb in most studies, but an increase in type IIa fibers with no change in type IIb fibers has also been reported. This shift in fiber proportion should help to preserve strength, but at the cost of increased fatigability and reduced muscle endurance. However, the relative proportion of fiber types had no independent effect on exercise capacity [12,13]. In addition to the shift in fiber type, there is a reduction in cross-sectional area of type I and type IIa fibers (ie muscle atrophy is present) .
Muscle capillarity is an important component of skeletal muscle oxidative capacity. The number of capillaries/mm2 was significantly lower in patients with COPD than in healthy control individuals . The ratio of capillary to fiber was also significantly lower in patients with COPD in one study , but this ratio did not reach statistical significance in another . The ratio of capillary to fiber did not improve following a physical training program .
Several studies in which the quadriceps muscle was biopsied [16,17] showed a reduction in oxidative enzyme capacity in patients with COPD as compared with control individuals. Citrate synthase (an enzyme that is involved in the citric acid cycle) and, to a lesser extent, 3-hydroxyacyl coenzyme A dehydrogenase (an enzyme that is involved in β-oxidation of fatty acids) are both significantly reduced in patients with COPD. Citrate synthase activity significantly correlated with peak VO2, independently of lung function . In one study , phosphofructokinase (a glycolytic enzyme that is involved in anaerobic metabolism) was significantly increased in patients with COPD, but this finding was not confirmed in a subsequent study . Cytochrome oxidase (the terminal enzyme in the mitochondrial electron transport chain) activity was significantly increased in patients with COPD and resting hypoxemia . It had been believed that all oxidative enzymes would respond in a qualitatively similar fashion to deconditioning, training, etc. However, these results suggest that different oxidative enzymes may be regulated differently in patients with COPD.
Cellular bioenergetics can also be measured in vivo in humans by 31P magnetic resonance spectroscopy (MRS). The ratio of intracellular phosphocreatine to inorganic phosphate (Pi) is closely related to that of ATP to ADP, and is believed to be a useful measure of mitochondrial phosphorylation potential. Intracellular pH can also be measured using 31P-MRS. Recovery times for phosphocreatine after exercise have been used to assess mitochondrial density and function. A number of studies have utilized this technology in patients with COPD. However, in many of the studies patients were chronically hypoxic or had chronic hypercapnic, hypoxemic respiratory failure. The muscles usually studied are those in the forearm or calf, because these are the easiest muscles to position within the coil. More recently, technology has evolved that permits assessment of the quadriceps muscles during and after exercise. However, the ability to measure precisely the same area of the muscle with no pollution of the signal from adjacent muscles before, during, and after exercise is probably not as good for the quadriceps muscle as it is for the calf or forearm muscles. It should be remembered that lower limb muscles are particularly susceptible to deconditioning, and appear to be more impaired than upper limb muscles in patients with COPD.
In one study of the quadriceps muscle in normoxic patients with COPD , the Pi : phosphocreatine ratio was higher and intracellular pH lower in patients with COPD than in age-matched control individuals at the same absolute work rate. Similarly, the half-time for phosphocreatine recovery was significantly longer in the patients with COPD. These results provide further support that oxidative metabolism in the exercising muscle is impaired in patients with COPD. The increased Pi : phosphocreatine ratio and decreased intracellular pH during exercise were observed in previous studies in the forearm and calf muscles [21,22,23,24,25]. A prolonged half-time for phosphocreatine recovery was observed in some [22,24,25], but not all previous studies .
Blood lactate levels start to increase at very low work rates in patients with COPD [26,27]. Because blood flow to the leg is within normal limits in patients with COPD , the increase in lactate is due to an increase in net lactate output across the leg, probably because of increased lactate production within the exercising muscle. Oxygen delivery to the exercising leg is also not impaired in patients with COPD , suggesting that the increase in lactate production is due to an intrinsic muscle abnormality (reduced oxidative capacity) that results in early activation of anaerobic glycolysis.
Mechanisms of skeletal muscle dysfunction
Patients with COPD tend to reduce their level of physical activity because exertion causes unpleasant sensations. A vicious cycle can result, with reductions in physical activity producing more deconditioning, and more impairment in skeletal muscle function leading to more symptoms at lower levels of work. Inactivity produces a number of structural and biochemical changes [28,29,30]. Muscle mass decreases and type IIa fibers tend to convert to type IIb. A reduction in the proportion of type I fibers with prolonged inactivity has been reported . Oxidative enzyme concentration, the number and density of mitochondria, and the number of capillaries all decrease [28,29,30]. Reductions in oxidative capacity and muscle atrophy are common in patients with COPD. Deconditioning is almost certainly an important factor in the skeletal muscle dysfunction that is observed in patients with COPD.
Short courses of high-dose corticosteroids are used to treat acute exacerbations in patients with COPD. Low-dose oral corticosteroids have been used chronically to treat some patients with COPD, although the efficacy of this approach is hotly disputed. Steroid-induced myopathy has been well described, and may be more common than was initially appreciated. Histologically, both myopathic changes and generalized fiber atrophy are seen . In one study , survival of patients with steroid-induced myopathy was significantly lower than that in a matched group of patients with COPD and a similar degree of airflow obstruction. In a provocative study , the average daily dose of steroids was measured for 6 months in a group of patients with COPD or asthma. Only one patient was receiving daily steroids. The other patients received bursts of steroids for exacerbations of their disease. The average daily dose of steroids was only 4.3 mg (range 1.4–21.3 mg). Eight out of 21 patients had significant quadriceps weakness, as defined as a reduction in quadriceps force below the normal range. An average daily dose of steroids that exceeded 4 mg/day was more common in patients with quadriceps weakness than in those without. The average daily dose of steroids explained 51% of the variance in quadriceps force measurements. The results of this study were interpreted as indicating that bursts of steroids might cause peripheral muscle weakness. An alternative explanation is that patients with repetitive exacerbations are sicker, and therefore weaker than those without exacerbations.
Chronic hypoxia adversely affects skeletal muscles. With prolonged exposure to high-altitude hypoxia, glycolytic enzyme (which is active in anaerobic metabolism) activity increases, whereas oxidative enzyme activity decreases . Hypoxia also increases oxidative stress, which can adversely affect muscle performance . In animals, hypoxia leads to a reduction in muscle fiber diameter . Muscle fiber cross-sectional area is decreased in mountain climbers undergoing prolonged hypoxia (greater than 6 weeks) .
Short-term exposure to hypercapnia results in skeletal muscle weakness, but no change in fatigability [38,39]. In acute hypercapnic respiratory failure marked derangements in energy metabolism are seen, with marked reductions in ATP and phosphocreatine concentrations [40,41]. Acute hypercapnia also contributes to intracellular acidosis in patients with acute respiratory failure . The effects of chronic hypercapnia need to be delineated.
Nutritional depletion is common in patients with COPD. A commonly used definition of nutritional depletion is a body weight less than 90% of ideal body weight. Using this definition, 35% of patients entering a pulmonary rehabilitation program were nutritionally depleted . Body weight can be divided into fat and fat-free mass. Patients can be nutritionally depleted with a reduced fat-free mass, despite having a body weight within normal limits (due to an increased proportion of fat mass). Approximately 10% of patients meet this criteria .
A prolonged period of under-nutrition results in a reduction in muscle strength and endurance [43,44,45]. Under-nutrition results in a reduction in muscle mass and fiber atrophy [43,46]. Type II fibers are affected to a greater extent than are type I fibers [43,46]. Glycolytic and oxidative enzyme activity are both reduced [46,47]. Muscle bioenergetics may also be impaired; high ADP levels and reduced phosphocreatine levels after contraction have been reported in food-deprived animals [47,48].
Oxidative stress may also contribute to the skeletal muscle dysfunction that is observed in patients with COPD. Increased plasma concentrations of lipid peroxidation products have been observed in patients with COPD during acute exacerbations . The main source of these oxygen free radicals is mitochondria [50,51]. However, another source is immune cells activated by inflammation. Elevated tumor necrosis factor-α levels have been observed in patients with COPD and weight loss [52,53]. Susceptibility of a tissue to free radicals depends largely on the antioxidant status of the tissue . The antioxidant status of skeletal muscle may be impaired by disuse or chronic hypoxia, or both.
Deconditioning from disuse is believed to be a major contributing factor in the skeletal muscle dysfunction that is observed in patients with COPD. Therefore, exercise training in this setting should be helpful. In normal individuals, an endurance training program produces a number of morphologic and physiologic changes within the exercising muscle that increase its aerobic capacity . These changes include an increase in mitochondrial number, increased muscle capillarization, and an increase in muscle oxidative enzyme activity. After intense training the proportion of type I fibers increases, whereas type IIb fibers can transform to type IIa . In order for an endurance-training program to produce these results, exercise must be above a critical minimum intensity (the minimum intensity has not been precisely defined, but exercise at 50–60% of maximal VO2 is clearly above it), and must be of sufficient duration and frequency .
It was formerly believed that patients with COPD could not perform exercise at a sufficient intensity (ie above the critical minimum intensity) to produce physiologic adaptations within the exercising muscle. In a previous study , muscle oxidative enzyme activity did not change after exercise training in a group of patients with COPD. However, the patients exercised at a relatively low intensity, even for patients with COPD. When patients with COPD underwent a more intensive training regimen an increase in oxidative enzyme activity was observed after training, clearly showing that patients with COPD can exercise sufficiently to undergo adaptations in the exercising muscle .
In a study that employed 31P-MRS in the quadriceps muscle  an improvement in cellular bioenergetics was observed after pulmonary rehabilitation. For the same duration and intensity of submaximal exercise, the Pi : phosphocreatine ratio decreased and intracellular pH increased as compared with before rehabilitation. Similarly, the half-time of phosphocreatine recovery decreased after pulmonary rehabilitation. These improvements in bioenergetic state are consistent with an improved mitochondrial oxidative capacity. Quadriceps endurance has been assessed in patients with COPD by performing repeated dynamic contractions until exhaustion at different power outputs. After pulmonary rehabilitation endurance time was significantly increased at all power outputs, indicating that quadriceps endurance was improved after rehabilitation . We measured quadriceps fatigability before and after pulmonary rehabilitation in 21 patients with COPD . Quadriceps contractile fatigue was assessed by measurement of quadriceps twitch force during supramaximal magnetic stimulation of the femoral nerve before and after constant load cycle exercise. For the same duration and intensity of exercise, the degree of exercise-induced quadriceps fatigue was significantly decreased after pulmonary rehabilitation. Thus, pulmonary rehabilitation resulted in increased fatigue resistance in the quadriceps muscle.
It is clear that exercise training can improve skeletal muscle function in patients with COPD. Exercise training (pulmonary rehabilitation) was shown to improve endurance exercise capacity and quality of life in patients with COPD [59,60]. Further studies are required to determine whether improvements in skeletal muscle function are responsible for the improvements in endurance exercise capacity and quality of life after pulmonary rehabilitation. In addition, the methodology of exercise training needs to be further studied. Some studies [26,61] have shown that (for the same total work) exercise at high intensity produces more benefits than exercise at lower levels of intensity. These results differ from those obtained in normal individuals. In normal persons, as long as the work intensity is above a critical minimum intensity, it is the total work performed and not the intensity of exercise that determines the training response . Whether the addition of strength training and/or upper limb training provides any additional benefits when added to lower limb endurance training requires further study . In one study , the addition of strength training did not provide any further benefits.
Hypoxia reduces exercise performance in patients with COPD. Possible mechanisms include reduced oxygen delivery to the exercising muscle and increased ventilatory requirements. Exercise performance improves in hypoxemic patients with COPD when supplemental oxygen is administered [65,66]. As described above, chronic hypoxia can adversely affect skeletal muscle function. It has not yet been determined whether the effects of chronic hypoxia can be reversed by long-term oxygen therapy.
In one study  an increase in the creatine phosphate/creatine phosphate+creatine ratio (measured from quadriceps muscle biopsy) was observed after long-term oxygen therapy in patients with COPD, suggesting a possible improvement in skeletal muscle energy metabolism. The same investigators did not observe any change in oxidative enzyme activity after long-term oxygen therapy . During exercise, acute administration of supplemental oxygen to hypoxemic patients with COPD improved aerobic metabolism, as measured using MRS [24,68]. Long-term oxygen therapy could also help by allowing patients to be more active, thereby reducing the effects of deconditioning. However, in one study  patients with COPD who desaturated during exercise were randomized to receive supplemental oxygen or air during exercise in the context of a formal pulmonary rehabilitation program. Exercise performance and quality of life improved in both groups, with no significant differences between the groups.
Because oral steroids have a deleterious effect on skeletal muscle function, their use should be avoided whenever possible. The efficacy of chronic oral steroid therapy in stable patients with COPD is controversial at best. If chronic oral therapy is contemplated, it should be clear that simpler, less toxic therapeutic options have failed. Chronic therapy should only be continued if a clear unambiguous response to a trial of therapy is observed. The majority of patients will not show such a response . In contrast, administration of steroids during an acute exacerbation is beneficial . Two weeks of therapy was just as effective as 8 weeks of therapy, indicating that a prolonged taper of steroid dosage is not required. The long-term effects of short bursts of high-dose steroids require further study.
Because nutritional depletion has been associated with a poorer outcome in patients with COPD [72,73], nutritional repletion has been attempted. The results of this intervention have not been encouraging. In a recent meta-analysis , nutritional support had no significant effect on weight gain, anthropometric measures, FEV1, respiratory muscle strength, or 6-min walk distance. It was often difficult to increase caloric intake substantially in outpatients with COPD because many of the patients tended to decrease their spontaneous intake of food in proportion to the degree of supplementation. In one study , patients were fed enterally via percutaneous gastrostomy. Caloric intake was greater than two times the resting energy expenditure. Patients gained weight, but the majority of weight gained was fat and there was no significant change in lean body mass. These results demonstrate that nutritional support alone is not usually successful in increasing lean body mass in patients with COPD.
Recent evidence [52,53] suggests that, in some nutritionally depleted patients with COPD, weight loss may be related to a systemic catabolic response induced by inflammation. In such patients, it is believed that nutritional support will not address the underlying problem, and therefore will not be effective. In a relatively large study , nutritional supplementation was administered while patients underwent an inpatient pulmonary rehabilitation program. Despite relatively modest nutritional supplementation, patients increased weight and, to a lesser extent, fat-free mass as compared with a control group. Despite the positive results for the group as a whole, many patients did not gain weight with this approach. Unfortunately, limb muscle strength and quality of life were not measured. Inspiratory muscle strength was measured and did not significantly improve in the nutritionally supported group. Distance walked in 12 min improved in all groups (all of the patients were undergoing an exercise training program). There was no significant difference in the degree of improvement between the patients who were nutritionally supported and the control group who were not. The combined effects of nutritional supplementation and exercise training in nutritionally depleted patients with COPD require further study.
Anabolic hormones are important mediators of muscle growth. Deficiencies in anabolic hormones lead to muscle wasting. Because anabolic hormones can be exogenously supplemented, this is an important area of research. Two hormone systems that are known to effect muscle — growth hormone and anabolic steroids — have been studied in patients with COPD.
Growth hormone exerts its effects primarily by increasing levels of insulin-like growth factors. In growth hormone-deficient adults, administration of growth hormone increases muscle mass and strength, and improves exercise performance [77,78]. Administration of growth hormone to healthy elderly individuals increases muscle mass, but not muscle strength or endurance [79,80]. Two controlled studies [81,82] examined whether administration of growth hormone would increase the benefits of exercise training in patients with COPD. In both studies, the group that received growth hormone plus exercise training increased lean body mass, whereas the group that received exercise training alone did not. In one study  muscle cross-sectional area was measured, and increased in the growth hormone group. Despite the increase in muscle mass, no significant change in maximal inspiratory muscle strength was observed [81,82]. The only measure of peripheral muscle strength obtained was handgrip strength, which did not change with exercise training in either the growth hormone or control group . There were no significant differences between groups in the improvements after training in peak exercise capacity, whereas the improvements in endurance exercise were not significantly different between groups in one study , and were significantly less in the growth hormone group in the other . Growth hormone is extremely expensive, and the data to date do not support its use in patients with COPD.
In hypogonadal men, testosterone replacement increases muscle mass and strength [83,84]. Although anabolic steroids have been used by competitive athletes for years to enhance performance, the effects of these agents in eugonadal men remained controversial. Recently, it was unambiguously shown  that anabolic steroids will increase muscle size and strength in healthy eugonadal men. Elderly men with mildly depressed testosterone levels may respond to anabolic steroids by increasing body weight and muscle strength .
Low testosterone levels are relatively common in patients with COPD . The effects of anabolic steroids in patients with COPD with low testosterone levels have not been evaluated. Two studies [76,88] evaluated the effects of anabolic steroids in patients with COPD undergoing pulmonary rehabilitation [76,88]. In one of the studies the patients received nutritional supplementation in addition to anabolic steroids. In both studies, there was a significant increase in weight and lean body weight with anabolic steroids as compared with a control group. Maximal inspiratory muscle strength increased significantly in the anabolic steroid group in one study, but not in the other. Measurements of limb muscle strength were not performed. In the one study in which these parameters were measured , peak exercise capacity and 6-min walk distance were not significantly improved in either the anabolic steroid or the control group after pulmonary rehabilitation. Improvements in peripheral muscle strength usually do not result in an improvement in endurance exercise performance. When strength training was added to an endurance exercise program in patients with COPD the limb muscles did become stronger, but this increase in strength did not result in any additional improvement in exercise performance or quality of life .
Skeletal muscle dysfunction is very common in patients with COPD, and may play an important role in limiting exercise performance in these patients. Muscle strength and endurance are both decreased and the muscle is more easily fatigued. Muscle atrophy is largely responsible for the reduction in muscle strength. Changes in fiber type, reduced capillarity, decreased oxidative enzyme capacity, and altered cellular bioenergetics have all been documented in patients with COPD, and can potentially explain the reduction in muscle endurance. Mechanistically, deconditioning is of major importance. Other factors that are probably important in individual patients include hypoxia or hypercapnia, nutritional depletion, and steroid use. COPD may also produce a systemic inflammatory response that may adversely affect skeletal muscle function, but more work is required to substantiate this hypothesis. Exercise therapy has been shown to improve skeletal muscle function. Other potential therapies, such as oxygen supplementation, nutritional repletion, and administration of anabolic steroids, require further study.
chronic obstructive pulmonary disease
forced expiratory volume in 1 s
magnetic resonance spectroscopy
Bernard S, LeBlanc P, Whittom F, Carrier G, Jobin J, Belleau R, Maltais F: Peripheral muscle weakness in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998, 158: 629-634.
Hamilton AL, Killian KJ, Summers E, Jones NL: Muscle strength, symptom intensity, and exercise capacity in patients with car-diorespiratory disorders. Am J Respir Crit Care Med. 1995, 152: 2021-2031.
Gosselink R, Troosters T, DeCramer M: Peripheral muscle weakness contributes to exercise limitation in COPD. Am J Respir Crit Care Med. 1996, 153: 976-980.
Serres I, Gautier V, Varray A, Prefaut C: Impaired skeletal muscle endurance related to physical inactivity and altered lung function in COPD patients. Chest. 1998, 113: 900-905.
Zattara-Hartmann MC, Badier M, Guillot C, Tomei C, Jammes Y: Maximal force and endurance to fatigue of respiratory and skeletal muscles in chronic hypoxemic patients: the effects of oxygen breathing. Muscle Nerve. 1995, 18: 495-502.
Newell SZ, McKenzie DK, Gandevia SC: Inspiratory and skeletal muscle strength and endurance and diaphragmatic activation in patients with chronic airflow limitation. Thorax. 1989, 44: 903-912.
Mador MJ, Kufel TJ, Pineda L: Quadriceps fatigue after cycle exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000, 161: 447-453.
Kufel TJ, Pineda LA, Mador MJ: Comparison of potentiated and unpotentiated twitches as an index of contractile fatigue [abstract]. Am J Respir Crit Care Med. 1998, 157: A215-
Mador MJ, Kufel TJ, Pineda LA, Steinwald A, Aggarwal A, Upadhyay AM, Khan MA: Effect of pulmonary rehabilitation on quadriceps fatigability during exercise. Am J Respir Crit Care Med. 2001, 163: 930-935.
Mador MJ, Kufel TJ, Pineda LA: Quadriceps and diaphragmatic function after exhaustive cycle exercise in the healthy elderly. Am J Respir Crit Care Med. 2000, 162: 1760-1766.
Whittom F, Jobin J, Simard PM, LeBlanc P, Simard C, Bernard S, Belleau R, Maltais F: Histochemical and morphological characteristics of the vastus lateralis muscle in patients with chronic obstructive pulmonary disease. Med Sci Sports Exerc. 1998, 30: 1467-1474. 10.1097/00005768-199810000-00001.
Maltais F, Sullivan MJ, LeBlanc P, Duscha BD, Schachat FH, Simard C, Blank JM, Jobin J: Altered expression of myosin heavy chain in the vastus lateralis muscle in patients with COPD. Eur Respir J. 1999, 13: 850-854. 10.1183/09031936.99.13485099.
Satta A, Migliori GB, Spanevello A, Neri M, Bottinelli R, Canepari M, Pellegrino MA, Reggiani C: Fiber types in skeletal muscles of chronic obstructive pulmonary disease patients related to respiratory function and exercise tolerance. Eur Respir J. 1997, 10: 2853-2860. 10.1183/09031936.97.10122853.
Jobin J, Maltais F, Doyon JF, LeBlanc P, Simard PM, Simard AA, Simard : Chronic obstructive pulmonary disease capillarity and fiber-type characteristics of skeletal muscle. J Cardiopulm Rehab. 1998, 18: 432-437. 10.1097/00008483-199811000-00005.
Jakobsson P, Jorfeldt L, Brundin A: Skeletal muscle metabolites and fiber types in patients with advanced chronic obstructive pulmonary disease (COPD), with and without chronic respiratory failure. Eur Respir J. 1990, 3: 192-196.
Jakobsson P, Jorfeldt L, Henriksson J: Metabolic enzyme activity in the quadriceps femoris muscle in patients with severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1995, 151: 374-377.
Maltais F, Simard AA, Simard C, Jobin J, Desgagnes P, LeBlanc P: Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD. Am J Respir Crit Care Med. 1996, 153: 288-293.
Maltais F, LeBlanc P, Whittom F, Simard C, Marquis K, Belanger M, Breton M-J, Jobin J: Oxidative enzyme activities of the vastus lateralis muscle and the functional status in patients with COPD. Thorax. 2000, 55: 848-853. 10.1136/thorax.55.10.848.
Sauleda J, Garcia-Palmer F, Wiesner RJ, Tarraga S, Harting I, Tomas P, Gomez C, Saus C, Palou A, Agusti AGN: Cytochrome oxidase activity and mitochondrial gene expression in skeletal muscle of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998, 157: 1413-1417.
Sala E, Roca J, Marrades RM, Alonso J, Gonzalez de Suso JM, Moreno A, Barbera JA, Nadal J, de Jover L, Rodriguez-Roisin R, Wagner PD: Effects of endurance training on skeletal muscle bioenergetics in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999, 159: 1726-1734.
Kutsuzawa T, Shioya S, Kurita D, Haida M, Ohta Y, Yamabayashi H: Muscle energy metabolism and nutritional status in patients with chronic obstructive pulmonary disease. A 31P magnetic resonance study. Am J Respir Crit Care Med. 1995, 152: 647-652.
Tada H, Kato H, Misawa T, Sasaki F, Hayashi S, Takahashi Y, Kutsumi Y, Ishizaki T, Nakai T, Miyabo S: 31P-nuclear magnetic resonance evidence of abnormal skeletal muscle metabolism in patients with chronic lung disease and congestive heart failure. Eur Respir J. 1992, 5: 163-169.
Thompson CH, Davies RJO, Kemp GJ, Taylor DJ, Radda GK, Rajagopalan B: Skeletal muscle metabolism during exercise and recovery in patients with respiratory failure. Thorax. 1993, 48: 486-490.
Payen JF, Wuyam B, Levy P, Reutenauer H, Stieglitz P, Paramelle B, Le Bas J-F: Muscular metabolism during oxygen supplementation in patients with chronic hypoxemia. Am Rev Respir Dis. 1993, 147: 592-598.
Wuyam B, Payen JF, Levy P, Bensaidane H, Reutenauer H, LeBas JF, Benabid AL: Metabolism and aerobic capacity of skeletal muscle in chronic respiratory failure related to chronic obstructive pulmonary disease. Eur Respir J. 1992, 5: 157-162.
Casaburi R, Patessio A, Ioli F, Zanaboni S, Donner CF, Wasserman K: Reductions in exercise lactic acidosis and ventilation as a result of exercise training in patients with obstructive lung disease. Am Rev Respir Dis. 1991, 143: 9-18.
Maltais F, Jobin J, Sullivan MJ, Bernard S, Whittom F, Killian KJ, Desmeules M, Belanger M, LeBlanc P: Metabolic and hemodynamic responses of lower limb during exercise in patients with COPD. J Appl Physiol. 1998, 84: 1573-1580.
Saltin B, Gollnick PD: Skeletal muscle adaptability: significance for metabolism and performance. In: Handbook of Physiology: Skeletal Muscle. Edited by Peachey LD. Washington, DC: American Physiological Society,. 1986, : 555-631.
Casaburi R: Deconditioning. In: Pulmonary Rehabilitation. Edited by Fishman AP. New York: Marcel Dekker,. 1996, : 213-230.
Coyle EF, Martin WH, Bloomfield SA, Lowry DH, Holloszy JO: Effects of detraining on responses to submaximal exercise. J Appl Physiol. 1985, 59: 853-859.
Larsson L, Ansved T: Effects of long-term physical training and detraining on enzyme histochemical and functional skeletal muscle characteristic in man. Muscle Nerve. 1985, 8: 714-722.
Decramer M, de Bock V, Dom R: Functional and histologic picture of steroid-induced myopathy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1996, 153: 1958-1964.
Decramer M, Lacquet LM, Fagard R, Rogiers P: Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir Crit Care Med. 1994, 150: 11-16.
Howald H, Pette D, Simoneau JA, Uber A, Hoppeler H, Cerretelli P: Effect of chronic hypoxia on muscle enzyme activities. Int J Sports Med. 1990, 11: 510-514.
Corbucci GG, Menichetti A, Cogliati A, Ruvolo C: Metabolic aspects of cardiac and skeletal muscle tissues in the condition of hypoxia, ischaemia and reperfusion induced by extra-corporeal circulation. Int J Tissue React. 1995, 17: 219-225.
Bigard AX, Brunet A, Guezennec CY, Monod H: Effects of chronic hypoxia and endurance training on muscle capillarity in rats. Pflugers Arch. 1991, 419: 225-229.
Hoppeler H, Kleinert E, Schlegel C, Claassen H, Howald H, Kayar SR, Cerretelli P: Morphological adaptations of human skeletal muscle to chronic hypoxia. Int J Sports Med. 1990, 11(suppl 1): S3-S9.
Mador MJ, Wendel T, Kufel TJ: Effect of acute hypercapnia on diaphragmatic and limb muscle contractility. Am J Respir Crit Care Med. 1997, 155: 1590-1595.
Vianna LG, Koulouris N, Lanigan C, Moxham J: Effect of acute hypercapnia on limb muscle contractility in humans. J Appl Physiol. 1990, 69: 1486-1493.
Gertz I, Hedenstierna G, Hellers G, Wahren J: Muscle metabolism in patients with chronic obstructive lung disease and acute respiratory failure. Clin Sci Mol Med. 1977, 52: 396-403.
Fiaccadori E, Del Canale S, Vitali P, Coffrini E, Ronda N, Guariglia A: Skeletal muscle energetics, acid-base equilibrium and lactate metabolism in patients with severe hypercapnia and hypoxemia. Chest. 1987, 92: 883-887.
Schols AMWJ, Soeters PB, Dingemans AMC, Mostert R, Frantzen PJ, Wouters EFM: Prevalence and characteristics of nutritional depletion in patients with stable COPD eligible for pulmonary rehabilitation. Am Rev Respir Dis. 1993, 147: 1151-1156.
McLoughlin DM, Spargo E, Wassif WS, Newham DJ, Peters TJ, Lantos PL, Russell GF: Structural and functional changes in skeletal muscle in anorexia nervosa. Acta Neuropathol. 1998, 95: 632-640. 10.1007/s004010050850.
Engelen MAM, Schols AMWJ, Baken WC, Wesseling GJ, Wouters EFM: Nutritional depletion in relation to respiratory and peripheral skeletal muscle function in an outpatient population with chronic obstructive pulmonary disease. Eur Respir J. 1994, 7: 1793-1797. 10.1183/09031936.94.07101793.
Lopes J, Russell DM, Whitwell J, Jeejeebhoy KN: Skeletal muscle function in malnutrition. Am J Clin Nutr. 1982, 36: 602-610.
Essen B, Fohlin L, Thoren C, Saltin B: Skeletal muscle fiber types and sizes in anorexia nervosa patients. Clin Physiol. 1981, 1: 395-403.
Mijan de la Torre A, Madapallimattam A, Cross A, Armstrong RL, Jeejeebhoy KN: Effect of fasting, hypocaloric feeding, and refeeding on the energetics of stimulated rat muscle as assessed by nuclear magnetic resonance spectroscopy. J Clin Invest. 1993, 92: 114-121.
Russell DM, Atwood HL, Whittaker JS, Itakura T, Walker PM, Mickle DA, Jeejeebhoy KN: The effect of fasting and hypocaloric diets on the functional and metabolic characteristics of rat gastrocnemius muscle. Clin Sci. 1984, 67: 185-194.
Rahman I, Morrison D, Donaldson K, Macnee W: Systemic oxidative stress in asthma, COPD, and smokers. Am J Respir Crit Care Med. 1996, 154: 1055-1060.
Ji LL: Exercise, oxidative stress, and antioxidants. Am J Sports Med. 1996, 24: 520-524.
Giuliani A, Cestaro B: Exercise, free radical generation and vitamins. Eur J Cancer Prev. 1997, 6: 555-567.
Di Francia M, Barbier D, Mege JL, Orehek J: Tumor necrosis factor-a levels and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1994, 150: 1453-1455.
de Godoy I, Donahoe M, Calhoun WJ, Mancino J, Rogers RM: Elevated TNF-alpha production by peripheral blood monocytes of weight-losing COPD patients. Am J Respir Crit Care Med. 1996, 153: 633-637.
Howard H, Hoppeler H, Claassen H, Mathieu O, Stroub R: Influences of endurance training on the ultrastructural composition of the different muscle fiber types in humans. Pflugers Arch. 1985, 403: 369-376.
American College of Sports Medicine: The recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness in healthy adults. Med Sci Sports Exerc. 1990, 22: 265-274.
Belman MJ, Kendregan BA: Exercise training fails to increase skeletal muscle enzymes in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis. 1981, 123: 256-261.
Maltais F, LeBlanc P, Simard C, Jobin J, Berube C, Bruneau J, Carrier L, Belleau R: Skeletal muscle adaptation to endurance training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1996, 154: 442-447.
Serres I, Varray A, Vallet G, Micallef JP, Prefaut C: Improved skeletal muscle performance after individualized exercise training in patients with chronic obstructive pulmonary disease. J Cardiopulm Rehab. 1997, 17: 232-238. 10.1097/00008483-199707000-00003.
Ries AL, Kaplan RM, Limberg TM, Prewit LM: Effect of pulmonary rehabilitation on physiologic and psychological outcomes in patients with chronic obstructive pulmonary disease. Ann Intern Med. 1995, 122: 823-832.
Goldstein RS, Gort ED, Stubbing D, Avendano MA, Guyatt GH: Randomized controlled trial of respiratory rehabilitation. Lancet. 1994, 344: 1394-1397. 10.1016/S0140-6736(94)90568-1.
Casaburi R, Porszasz J, Burns MR, Carithers E, Chang RSY, Cooper CB: Physiologic benefits of exercise training in rehabilitation of patients with severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1997, 155: 1541-1551.
Casaburi R, Storer TW, Sullivan CS, Wasserman K: Evaluation of blood lactate elevation as an intensity criterion for exercise training. Med Sci Sports Exerc. 1995, 27: 852-862.
Lacasse Y, Guyatt GH, Goldstein RS: The components of a respiratory rehabilitation program. A systematic overview. Chest. 1997, 111: 1077-1088.
Bernard S, Whittom F, LeBlanc P, Jobin J, Belleau R, Berube C, Carrier G, Maltais F: Aerobic and strength training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999, 159: 896-901.
Cotes JE, Gilson JC: Effect of oxygen on exercise ability in chronic respiratory insufficiency. Lancet. 1956, 1: 872-876. 10.1016/S0140-6736(56)91341-1.
Stein DA, Bradley BL, Miller WC: Mechanisms of oxygen effects on exercise in patients with chronic obstructive pulmonary disease. Chest. 1982, 81: 6-10.
Jakobsson P, Jorfeldt L: Long-term oxygen therapy may improve skeletal muscle metabolism in advanced chronic obstructive pulmonary disease patients with chronic hypoxemia. Respir Med. 1995, 89: 471-476.
Mannix ET, Boska MD, Galassetti P, Burton G, Manfredi F, Farber MO: Modulation of ATP production by oxygen in obstructive lung disease as assessed by 31P-MRS. J Appl Physiol. 1995, 78: 2218-2227.
Rooyackers JM, Dekhuijzen PN, Van Herwaarden CL, Folgering HT: Training with supplemental oxygen in patients with COPD and hypoxemia at peak exercise. Eur Respir J. 1997, 10: 1278-1284. 10.1183/09031936.97.10061278.
Callahan CM, Dittus RS, Katz BP: Oral corticosteriod therapy for patients with stable chronic obstructive pulmonary disease. A meta-analysis. Ann Intern Med. 1991, 114: 216-223.
Niewoehner DE, Erbland ML, Deupree RH, Collins D, Gross NJ, Light RW, Anderson P, Morgan NA: Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med. 1999, 340: 1941-1947. 10.1056/NEJM199906243402502.
Gray-Donald K, Gibbons L, Shapiro SH, Macklem PT, Martin JG: Nutritional status and mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1996, 153: 961-966.
Shoup R, Dalsky G, Warner S, Davies M, Connors M, Khan M, Khan F, ZuWallack R: Body composition and health-related quality of life in patients with obstructive airways disease. Eur Respir J. 1997, 10: 1576-1580. 10.1183/09031936.97.10071576.
Ferreira IM, Brooks D, Lacasse Y, Goldstein RS: Nutritional support for individuals with COPD. A meta-analysis. Chest. 2000, 117: 672-678. 10.1378/chest.117.3.672.
Donahoe M, Mancino J, Costantino J, Lebow H, Rogers RM: The effect of an aggressive nutritional support regimen on body composition in patients with severe COPD and weight loss [abstract]. Am J Respir Crit Care Med. 1994, 149: A313-
Schols AMWJ, Soeters PB, Mostert R, Pluymers RJ, Wouters EFM: Physiologic effects of nutritional support and anabolic steroids in patients with chronic obstructive pulmonary disease. A placebo-controlled randomized trial. Am J Respir Crit Care Med. 1995, 152: 1268-1274.
Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH: Growth hormone treatment in growth hormone-deficient adults. I. Effects on muscle mass and strength. J Appl Physiol. 1991, 70: 688-694.
Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH: Growth hormone treatment in growth hormone-deficient adults. Il. Effects on exercise performance. J Appl Physiol. 1991, 70: 695-700.
Taaffe DR, Pruitt L, Reim J, Hintz RL, Butterfield G, Hoffman AR, Marcus R: Effect of recombinant human growth hormone on the muscle strength response to resistance exercise in elderly men. J Clin Endocrinol Metab. 1994, 79: 1361-1366.
Papadakis MA, Grady D, Black D, Tierney MJ, Gooding GA, Schambelan M, Grunfeld C: Growth hormone replacement in healthy older men improves body composition but not functional ability. Ann Intern Med. 1996, 124: 708-716.
Burdet L, de Muralt B, Schutz Y, Pichard C, Fitting JW: Administration of growth hormone to underweight patients with chronic obstructive pulmonary disease. A prospective, randomized, controlled study. Am J Respir Crit Care Med. 1997, 156: 1800-1806.
Casaburi R, Carithers E, Tosolini J, Phillips J, Bhasin S: Randomized placebo controlled trial of growth hormone in severe COPD patients undergoing endurance exercise training [abstract]. Am J Respir Crit Care Med. 1997, 155: A498-
Bhasin S, Storer TW, Berman N, Yarasheski KE, Clevenger B, Phillips J, Lee WP, Bunnell TJ, Casaburi R: Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab. 1997, 82: 407-413.
Sih R, Morley JE, Kaiser FE, Perry HM, Patrick P, Ross C: Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 1997, 82: 1661-1667.
Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A, Casaburi R: The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996, 335: 1-7. 10.1056/NEJM199607043350101.
Urban RJ, Bodenburg YH, Gilkison C, Foxworth J, Coggan AR, Wolfe RR, Ferrando A: Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol. 1995, 269: E820-E826.
Segal JM, Laghi F, Choe W, Desai K, Jubran A, Tobin MJ: Prevalence of hypogonadism in patients with chronic obstructive pulmonary disease [abstract]. Am J Respir Crit Care Med. 2000, 161: A232-
Ferreira IM, Verreschi IT, Nery LE, Goldstein RS, Zamel N, Brooks D, Jardim JR: The influence of 6 months of oral anabolic steroids on body mass and respiratory muscles in undernourished COPD patients. Chest. 1998, 114: 19-28.
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Jeffery Mador, M., Bozkanat, E. Skeletal muscle dysfunction in chronic obstructive pulmonary disease. Respir Res 2, 216 (2001). https://doi.org/10.1186/rr60
- lung diseases
- nutrition disorder