Peripheral muscle alterations in non-COPD smokers

Maria Montes de Oca, MD, PhD; Eduardo Loeb, MD; Sonia H. Torres, MD, PhD; Juan De Sanctis, PhD; Noelina Hernández, PhD and Carlos Tálamo, MD, FCCP

Disclosures

CHEST. 2008;133(1):13-18. 

In This Article

Abstract and Introduction

Background: Although tobacco smoke is the main cause of COPD, relatively little attention has been paid to its potential damage to skeletal muscle. This article addresses the effect of smoking on skeletal muscle.
Methods: The vastus lateralis muscle was studied in 14 non-COPD smokers (FEV1/FVC, 78 ± 5%) and 20 healthy control subjects (FEV1/FVC, 80 ± 3%). Muscular structure, enzyme activity, constitutive and inducible nitric oxide (NO) synthases (endothelial NO oxide synthase [eNOS], neuronal NO synthase [nNOS] and inducible NO synthase [iNOS]), nitrites, nitrates, nitrotyrosine, and the presence of macrophages were analyzed.
Results: In smokers, type I muscle fibers cross-sectional area was decreased, and a similar trend was found in type IIa fibers. Lactate dehydrogenase levels and the percentage of fibers with low oxidative and high glycolytic capacity were increased in smokers. nNOS (96.9 ± 11.7 vs 125.4 ± 31.9 ng/mg protein; p < 0.01) and eNOS (38.9 ± 11.0 vs 45.2 ± 7.7 ng/mg protein [± SD]; p < 0.05) were lower in smokers, while fiber type distribution, capillarity measures, β-hydroxy-acyl-CoA-dehydrogenase levels, iNOS, nitrite, nitrate, and nitrotyrosine levels, and macrophage number in the muscle tissue were similar to the nonsmoker subjects.
Conclusions: Smokers presented some alterations of skeletal muscle such as oxidative fiber atrophy, increased glycolytic capacity, and reduced expression of the constitutive NO synthases (eNOS and nNOS). The findings support some muscular structural and metabolic damage but not the presence of local inflammation in the smokers. In addition, they suggest a possible effect of tobacco smoke impairing the normal process of NO generation.

Several studies[1,2,3,4,5] have shown that skeletal muscle function and structure are altered in COPD patients. Peripheral muscle dysfunction is probably the most studied systemic effect of COPD; however, the mechanisms responsible for its occurrence are still poorly understood. It is probably multifactorial in origin, and there is strong evidence suggesting a link with disuse, chronic hypoxia, nutritional abnormalities, and the development of systemic inflammation and oxidative stress.

Although it is accepted that tobacco smoke is the major cause of COPD, much less attention has been paid to its potential effect in the extrapulmonary manifestations of the disease. Tobacco smoke has > 4,700 compounds, including free radicals and other oxidants, which can be potentially harmful to skeletal muscle. In rats exposed to cigarette smoke, Nakatani et al[6,7] showed a reduced proportion of type I fibers and cross-sectional area (CSA) of type I and IIa fibers in soleus muscle, and decreased CSA of IIa and IIb fibers in extensor digitorum longus muscles. Orlander et al[8] studied the skeletal muscle characteristics in smokers and nonsmoking subjects. Their results indicated the presence of abnormalities in smokers characterized by a reduction of type I and increase in type IIb fibers, as well as reduced muscle oxidative capacity, findings similar to those reported in COPD patients. Unfortunately, pulmonary function was not performed in this study[8] ; therefore, it is not clear whether the differences are an effect of smoking per se or if some of the smokers had COPD.

An oxidant/antioxidant imbalance has been reported in active and passive smokers.[9,10,11,12] In addition, cigarette smoke exposure in experimental animals affects the antioxidative capacity of skeletal muscle.[13] There is also evidence that the activity of endothelial nitric oxide (NO) may be impaired in smokers.[14]

Motivated by the lack of information about the potential damage to the skeletal muscle of cigarette smoke, the present study was designed to compare skeletal muscle enzyme activity and morphologic characteristics between smokers with normal spirometry results and normal subjects. In addition, we investigated the concentration of endothelial NO synthase (eNOS), neuronal NO synthase (nNOS), and inducible NO synthase (iNOS), and the products of NO: nitrite, nitrate, and nitrotyrosine. The possible presence of macrophages was evaluated with anti-CD68 in the muscle of some of the subjects.

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