Two Weeks of Smoking Cessation Reverse Cigarette Smoke-Induced Skeletal Muscle Atrophy and Mitochondrial Dysfunction in Mice

Abstract

Introduction Apart from its adverse effects on the respiratory system, cigarette smoking also induces skeletal muscle atrophy and dysfunction. Whether short-term smoking cessation can restore muscle mass and function is unknown. We, therefore, studied the impact of 1- and 2-week smoking cessation on skeletal muscles in a mouse model. Methods Male mice were divided into four groups: Air-exposed (14 weeks); cigarette smoke (CS)-exposed (14 weeks); CS-exposed (13 weeks) followed by 1-week cessation; CS-exposed (12 weeks) followed by 2 weeks cessation to examine exercise capacity, physical activity levels, body composition, muscle function, capillarization, mitochondrial function and protein expression in the soleus, plantaris, and diaphragm muscles. Results CS-induced loss of body and muscle mass was significantly improved within 1 week of cessation due to increased lean and fat mass. Mitochondrial respiration and protein levels of the respiratory complexes in the soleus were lower in CS-exposed mice, but similar to control values after 2 weeks of cessation. Exposing isolated soleus muscles to CS extracts reduced mitochondrial respiration that was reversed after removing the extract. While physical activity was reduced in all groups, exercise capacity, limb muscle force, fatigue resistance, fiber size and capillarization, and diaphragm cytoplasmic HIF-1α were unaltered by CS-exposure. However, CS-induced diaphragm atrophy and increased capillary density were not seen after 2 weeks of smoking cessation. Conclusion In male mice, 2 weeks of smoking cessation reversed smoking-induced mitochondrial dysfunction, limb muscle mass loss, and diaphragm muscle atrophy, highlighting immediate benefits of cessation on skeletal muscles. Implications Our study demonstrates that CS-induced skeletal muscle mitochondrial dysfunction and atrophy are significantly improved by 2 weeks of cessation in male mice. We show for the first time that smoking cessation as short as 1 to 2 weeks is associated with immediate beneficial effects on skeletal muscle structure and function with the diaphragm being particularly sensitive to CS-exposure and cessation. This could help motivate smokers to quit smoking as early as possible. The knowledge that smoking cessation has potential positive extrapulmonary effects is particularly relevant for patients referred to rehabilitation programs and those admitted to hospitals suffering from acute or chronic muscle deterioration yet struggling with smoking cessation.

Fourteen days of smoking cessation improves muscle fatigue resistance and reverses markers of systemic inflammation

“…It should be noted, however, that TNF-α is not only produced by blood mononuclear cells, but also by epithelial cells, fibroblasts and smooth muscle cells 58 , p. 229 and perhaps mononuclear and epithelial cells in the lung of smokers 59 . In line with this, it has been observed that there was a significantly elevated number of macrophages and neutrophils in the broncheo-alveolar lavage fluid of smoking mice 26 . Therefore, lung-derived cytokines may well be the prime explanation of the higher TNF-α, IL-2, IL-4, IL-6 and IL-10 concentrations and the lower level of the anti-inflammatory IL-12p70 concentration in smokers than non-smokers, indicating that even young-adult asymptomatic smokers suffer from a low-grade systemic inflammation.…”

“…In fact, smoking cessation is considered one of the main actions to attenuate the progression of COPD 31 , 32 . In line with this, it has been seen in mice, that the smoking-induced lung inflammation, mitochondrial dysfunction, limb and diaphragm muscle atrophy, and elevated IL-1α and TNF-α levels were normalised after smoking cessation 26 , 33 . In addition, if CO is an important cause of a reduced muscle fatigue resistance and exercise tolerance, we expect that smoking cessation, resulting in a quick normalisation of the COHb levels 34 , will be associated with a concomitant improvement in muscle function.…”

“…The significance of elevated COHb levels has been illustrated by an acute CO-induced reduction in muscle fatigue resistance in healthy people 24 . In addition, CO and cyanide may also directly impair mitochondrial respiration 25 , 26 . As fatigue resistance was similar in COPD patients who had quit smoking and healthy age-matched non-smokers 27 , we hypothesised that the effect of smoking on skeletal muscle fatigue is readily reversible by smoking cessation .…”

Towards Personalized Management of Sarcopenia in COPD

“…Indeed, recently a study in mice demonstrated that short-term smoking cessation reversed smoking-induced mitochondrial dysfunction, limb muscle mass loss and diaphragm muscle atrophy. 161…”

Progressive Skeletal Muscle Atrophy in Muscular Dystrophies: A Role for Toll-Like Receptor-Signaling in Disease Pathogenesis

“…Healthy skeletal muscle tissue needs to adapt to an individual’s needs and physical activity by adjusting properties, size, and numbers of muscle fibers. The most obvious adaptation of muscle mass is associated with exercise, but other lifestyle factors, such as smoking [ 9 ], may also be of influence. Muscle mass and performance adaptation are under the dynamic control of factors involved in the regulation of protein expression and turnover.…”