Cigarette smoke-induced oxidative stress in skeletal muscles of mice
Highlights
► Oxidative stress was evaluated in muscles of AKR/J mice chronically exposed to CS. ► Lung emphysema developed in the CS-exposed mice. ► CS induced oxidation of metabolic and structural proteins in respiratory and limb muscles. ► Systemic inflammation was increased in response to chronic CS exposure. ► Chronic CS exposure induces lung emphysema together with muscle oxidative stress in mice.
Introduction
In patients with chronic conditions such as chronic obstructive pulmonary disease (COPD), skeletal muscle abnormalities are common systemic manifestations, leading to reduced exercise capacity, poor quality of life, and increased mortality (Anon, 1999, Swallow et al., 2007). Systemic inflammation and both systemic and local oxidative stress are counted among the most widely studied molecular mechanisms clearly contributing to muscle alterations in COPD patients (Anon, 1999, Barreiro et al., 2003, Barreiro et al., 2005a, Barreiro et al., 2005c, Barreiro et al., 2010, Marin-Corral et al., 2009, Schols et al., 1996, Van Helvoort et al., 2006). Additionally, the large number of oxidants contained in cigarette smoke (CS) may also exert direct deleterious effects on skeletal muscles through oxidative damage of key biological structures. In this regard, smokers have been shown to exhibit lower peripheral muscle fatigue-resistance than nonsmokers (Wust et al., 2008). In spontaneously hypertensive rats exposed to CS, proportions and sizes of muscle fibers were also modified in soleus and extensor digitorum longus muscles (Nakatani et al., 2002, Nakatani et al., 2003). Importantly, the vastus lateralis of smokers was also shown to exhibit a reduction in the content of constitutive nitric oxide synthases (NOS) together with a smaller size of the slow-twitch fibers and increased oxidative stress (Montes de Oca et al., 2008). The latter findings lead to the concept that CS-induced effects may be a relevant contributing factor to the skeletal muscle abnormalities seen in COPD patients.
Importantly, in a previous study (Barreiro et al., 2010), guinea pigs chronically exposed to CS developed increased oxidative stress, especially of functional proteins such as creatine kinase, in both respiratory and limb muscles earlier than the bronchiolar alterations. Furthermore, it has also been shown that the development of emphysema in mice chronically exposed to CS is highly dependent on the mouse strain and dose (Foronjy et al., 2006, Guerassimov et al., 2004, van der Strate et al., 2006, Yao et al., 2008). In this regard, the AKR/J strain was shown to be extremely susceptible to the development of emphysema, as measured by increases in the airspace enlargement and the elastic properties of the lung, after chronic exposure to CS (Guerassimov et al., 2004). Likewise, the cellular and molecular inflammatory response was also shown to be more prominent in the lungs of the AKR/J mice chronically exposed to CS than in the other mouse strains investigated in the study in question (Guerassimov et al., 2004). These findings led to the conclusion that in susceptible mouse strains, the effects of chronic CS on the development of lung emphysema and inflammation clearly resemble those encountered in patients with COPD (Guerassimov et al., 2004). Whether chronic exposure to CS induces oxidative modifications on proteins of respiratory and limb muscles of susceptible mice has never been previously explored. On this basis, the rationale for conducting the present investigation was to explore whether increased levels of oxidative stress also develop in the diaphragm and gastrocnemius muscles of susceptible mice chronically exposed to CS. Confirmation of the study hypothesis will mimic structural and molecular events shown to occur in a group of susceptible patients to develop severe COPD in terms of lung emphysema together with increased oxidative stress in both respiratory and peripheral muscles.
Accordingly, our objectives were specifically focused on the assessment of the effects of reactive oxygen species (ROS) on muscle proteins, using several indices of oxidative stress, to identify the oxidatively modified proteins in those muscles, and to determine levels of systemic inflammation in both respiratory and limb muscles of AKR/J mice exposed to CS for 6 months. Antioxidant mechanisms were also explored in those muscles. Additionally, the effects of chronic exposure to CS on the body weight and lung structure of the AKR/J mice were also investigated in the present study.
Section snippets
Animal experiments
Twenty-two male AKR/J mice (8 weeks old, The Jackson Laboratory, Bar Harbor, ME, USA) were used for the purpose of the study. Thirteen mice were exposed to the smoke of 2 standard research nonfiltered cigarettes (2R1; University of Kentucky, Lexington, KY, USA) every 24 h, 5 days/week for a continuous period of 6 months following previously published methodologies (Guerassimov et al., 2004, van der Strate et al., 2006). The whole body of the animals was exposed to CS as follows: exposure to the
Animal characteristics
As illustrated in Fig. 1, AKR/J mice exposed to CS for 3, 4, 5, and 6 months exhibited a significantly lesser increase in their body weights compared to the corresponding control animals. Indeed, at 6 months, the average body weights of control mice significantly differed from those observed in the CS-exposed animals (43.8 ± 2.3 g versus 35.6 ± 2.4 g, respectively, p < 0.001). Moreover, at 6 months, average weights of the gastrocnemius muscles in control and CS-exposed mice were 0.13 ± 0.009 0.12 ± 0.01,
Discussion
In the present study, a major novel finding is that chronic CS induces oxidative modifications within the respiratory and limb muscles of small rodents. A second novel finding is related to the proteomics identification of the nature of the oxidized proteins within the muscles of mice exposed to chronic CS. Thirdly, levels of protein oxidation within the diaphragm muscle were shown to be somehow associated with the degree of emphysema and systemic inflammation among the exposed mice. These are
Acknowledgments
This study has been supported by SEPAR 2004, SEPAR 2005, SEPAR 2009, NEUMOMADRID 2006, FIS06/1043, 2005-SGR01060, 2009-SGR00393, CIBERES (Instituto de Salud Carlos III, Ministerio de Sanidad) (Spain). Dr. Esther Barreiro was a recipient of the ERS COPD Research Award 2008.
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