Abstract
Skeletal muscle dysfunction is a common complication and an important prognostic factor in patients with chronic obstructive pulmonary disease (COPD). It is associated with intrinsic muscular abnormalities of the lower extremities, but it is not known whether there is an easy way to predict its presence. Using a mouse model of chronic cigarette smoke exposure, we tested the hypothesis that magnetic resonance spectroscopy allows us to detect muscle bioenergetic deficit in early stages of lung disease. We employed this technique to evaluate the synthesis rate of adenosine triphosphate (ATP) and characterize concomitant mitochondrial dynamics patterns in the gastrocnemius muscle of emphysematous mice. The fibers type composition and citrate synthase (CtS) and cytochrome c oxidase subunit IV (COX4) enzymatic activities were evaluated. We found that the rate of ATP synthesis was reduced in the distal skeletal muscle of mice exposed to cigarette smoke. Emphysematous mice showed a significant reduction in body weight gain, in the cross-sectional area of the total fiber and in the COX4 to CtS activity ratio, due to a significant increase in CtS activity of the gastrocnemius muscle. Taken together, these data support the hypothesis that in the early stage of lung disease, we can detect a decrease in ATP synthesis in skeletal muscle, partly caused by high oxidative mitochondrial enzyme activity. These findings may be relevant to predict the presence of skeletal bioenergetic deficit in the early stage of lung disease besides placing the mitochondria as a potential therapeutic target for the treatment of COPD comorbidities.
Highlights
Chronic obstructive pulmonary disease (COPD) is currently considered one of the leading causes of death worldwide and chronic cigarette smoke exposure (CSE) is the main etiological agent
We observed that body weight gain in CSE mice was significantly reduced compared to airexposed mice: 19.9 ± 0.5% in CTL mice (30.2 ± 0.3 g) versus 15.4 ± 0.3% in CSE mice (28.5 ± 0.4 g), p = 0.029
These findings would explain the reduced rate of muscle adenosine triphosphate (ATP) synthesis and the decreased in the COX4/citrate synthase (CtS) activity ratio by the increase in oxidative capacity (CtS activity) in the gastrocnemius of mice exposed to chronic CSE compared to air-exposed control mice
Summary
Chronic obstructive pulmonary disease (COPD) is currently considered one of the leading causes of death worldwide and chronic cigarette smoke exposure (CSE) is the main etiological agent. In COPD, systemic manifestations and comorbidities are characteristic features that clearly have a negative effect on the capacity to perform physical exercise and on the quality of life of these patients [1]. Impairment of both has been attributed to muscle dysfunction [2,3]. Loss of muscle mass or atrophy, especially in the lower extremities, is usually associated with impaired function of these muscles in COPD patients. It was shown that quadriceps muscle dysfunction occurs in a third of patients with COPD, even in the early stages of their disease [4]. It is known that muscular weakness of the extremities and decreased in muscle mass are important predictors of mortality in COPD, regardless of the severity of the respiratory condition [5,6,7]
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