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POINT-COUNTERPOINT
Centre de Recherche
Hôpital Laval
Institut Universitaire de Cardiologie et de
Pneumologie de l'Université Laval
Québec, Canada
e-mail: francois.maltais{at}med.ulaval.ca
Exercise intolerance is ubiquitous in patients suffering from chronic obstructive pulmonary disease (COPD). Functional impairment can be evidenced by a lower walking capacity and cycling endurance compared with age-matched healthy controls (26). Reduced functional status and low level of daily physical activity predict poor quality of life (24), high health care use (7), and mortality (9) in these patients. A comprehensive understanding of the mechanisms of exercise intolerance is therefore of utmost importance to impact on these adverse outcomes and modify the evolution of the functional impairment associated with COPD.
Respiratory impairment is not sufficient in itself to explain exercise intolerance in COPD. The weak correlation between FEV1 or inspiratory capacity and exercise tolerance implies that other factors must be involved (21, 14). In 1992, Killian and collaborators (15) published a landmark paper that draws attention to the impact of the lower limb muscles on exercise intolerance in COPD. They reported that leg discomfort was a frequent exercise-limiting symptom invoked by these patients after a standardized cycling protocol. This report was the foundation of the rationale used by scientists to investigate lower limb muscle dysfunction in COPD. At that time, no one could have predicted how vast this research area would develop.
Although the ventilatory system is clearly dysfunctional in COPD, we will demonstrate that peripheral limitation to exercise tolerance is frequent in patients with COPD. To persuade the reader, morphological, biochemical, and clinical evidences demonstrating causal relationship between lower limb muscle dysfunction and exercise limitation will be exposed. We will focus on the tolerance to submaximal exercises, which are particularly influenced by the function and aerobic capacity of the lower limb muscles (3).
Morphological and biochemical evidences of lower limb muscle dysfunction in COPD. The prevalence of lower limb muscle atrophy in COPD ranges from 21 to 45% depending on the population being investigated and its operational definition (23, 27). Unexpectedly, muscle atrophy can even be present in patients with normal body weight (27). Given that muscle strength is mostly determined by muscle mass, muscle weakness is therefore highly prevalent in COPD (4, 11). Patients with COPD also have a poor resistance to isolated leg exercises and increased susceptibility to muscle fatigue (16), two correlates of impaired exercise capacity (1). In parallel, altered muscle energy metabolism as assessed by 31phosphorus magnetic resonance spectroscopy (30) has also been correlated to reduced exercise capacity in patients with COPD (30).
Muscle atrophy and impaired energy production are accountable for muscle weakness and increased susceptibility to fatigue, two strong determinants of exercise capacity (13). The physiological link between weakness, leg fatigue, and exercise intolerance was elegantly illustrated by Hamilton and colleagues (12). They evaluated the relationship between the perception of leg fatigue, work capacity, and muscle strength in normal individuals and patients with lung diseases, most of whom had COPD. Three interrelated observations, valid in healthy individuals and patients with lung diseases, were made 1) for a given power output, the perception of leg fatigue was greater in weaker compared with stronger individuals, 2) peak exercise capacity was reduced in weak individuals, and 3) the strength of the quadriceps was a key determinant of exercise capacity, independent of the impairment in lung function.
Convincing biochemical data also support the thesis that lower limb muscle dysfunction is a major contributor to exercise intolerance in COPD. At the cellular level, several morphological and structural modifications have been observed in the quadriceps of patients with moderate to severe COPD (2). These changes substantially compromise the metabolic performance and work output of activated muscles during exercise. Specifically, the morphological changes observed include reduction in type I fiber proportion (28) as well as reduction in cross-sectional area (CSA) for type I and II fibers (10, 28) that is proportional to the reported reduction in mid-thigh cross-sectional area (4). This former observation suggests that contractile protein deficit is largely responsible for both muscle atrophy and weakness and thus contribute to impaired exercise capacity.
The muscle structural and energetic changes described in COPD involve a reduction in myosin heavy chain I proportion (19) and a decrease in oxidative enzyme activities (10, 17, 18), a strong determinant of muscle endurance (1). Reduced oxidative metabolism correlates significantly with peak exercise capacity independently of lung function impairment (17). Early reliance on glycolytic activity for the energy production results in higher accumulation of inorganic phosphate (30) and premature muscle acidosis from lactate production (18), two biochemical events compromising the ability to sustain repeated muscle contractions and exercise performance. These adaptations seen in COPD are indicative of a muscle tissue that is inappropriately adapted to sustain the metabolic and mechanical requirements of submaximal exercises as seen in daily functional activities and provide a strong muscular basis to lower limb muscle dysfunction and exercise intolerance in COPD.
Clinical evidences of lower limb muscle dysfunction in COPD. Exercise intolerance in COPD is the result of a complex interplay between central (ventilation, dynamic hyperinflation, dyspnea) and peripheral (muscle atrophy and weakness, fatigue) factors. Although the relative contribution of these components to exercise intolerance is difficult to sort out within a single patient, clinical models illustrating the role of the lower limb muscles are available.
Undisputable evidences of peripheral limitation in exercising patients with COPD were provided by Williams and collaborators (29), who found that exercise limitation persisted in single and double lung transplant recipients years after the surgery despite complete restoration of their ventilatory capacity.
Direct role of lower limb muscle dysfunction on exercise intolerance was evidenced by a study evaluating the impact of muscle fatigue on the exercise response to bronchodilation (22). In that study, the occurrence of contractile fatigue of the quadriceps after constant work rate cycling exercise prevented acute bronchodilation to translate into further improvement in exercise capacity. Patients with COPD complaining of leg fatigue as the main exercise-limiting symptom are also less likely to improve exercise tolerance following bronchodilation compared with those stopping because of dyspnea (8). These studies, together with the observation described above in lung transplantation, nicely illustrate how proximal peripheral limitation to exercise prevents interventions aimed at improving lung function to translate into better functional status.
Pulmonary rehabilitation exemplifies how an intervention aimed at improving muscle function has a direct and significant positive impact on exercise tolerance. The consistent improvement in exercise tolerance reported with rehabilitation cannot be attributed to changes in respiratory function but rather to its global effects on lower limb muscle function characterized by improved strength, lesser susceptibility to fatigue, and better aerobic capacity (20). To some extent, these muscular physiological benefits also contribute to the reduction in ventilatory requirements, dynamic hyperinflation, and dyspnea often seen after exercise training (5, 6). In fact, better lower limb muscle function represents the physiological foundation of exercise training in COPD (25).
Conclusion. Lower limb muscles in COPD are atrophied, weak, fatigable, and metabolically inefficient. These unfavorable muscle characteristics concur to limit exercise capacity, a most debilitating feature in COPD. Taken as a whole, clinical observation and research work performed in several laboratories support the notion that lower limb muscle dysfunction is largely responsible for exercise limitation in COPD. Denying this obvious concept and omitting this relevant component of the disease will disservice our patients since lower limb muscle dysfunction can be, in contrast to lung impairment, amenable to therapy by rehabilitative strategies.
GRANTS
F. Maltais and R. Debigaré are research scholars of the Fonds de la Recherche en Santé du Québec. This work was supported by CIHR Grant No. MOP-84091.
REFERENCES
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  M. Decramer Response of the respiratory muscles to rehabilitation in COPD J Appl Physiol, September 1, 2009; 107(3): 971 - 976. [Abstract] [Full Text] [PDF]
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 G. R. Chiappa, F. Queiroga Jr., E. Meda, L. F. Ferreira, F. Diefenthaeler, M. Nunes, M. A. Vaz, M. C. L. Machado, L. E. Nery, and J. A. Neder Heliox Improves Oxygen Delivery and Utilization during Dynamic Exercise in Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., June 1, 2009; 179(11): 1004 - 1010. [Abstract] [Full Text] [PDF]
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J. B. West, P. D. Wagner, J. A. Neder, G. L. Scano, N. L. Jones, S. G. Zakynthinos, I. Vogiatzis, L. Nici, P. M. Calverley, H. R. Gosker, et al. The major limitation to exercise performance in COPD is inadequate energy supply to the respiratory and locomotor muscles vs. lower limb muscle dysfunction vs. dynamic hyperinflation J Appl Physiol, August 1, 2008; 105(2): 758 - 762. [Full Text] [PDF]
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