Cigarette smoke exposure induces diaphragm atrophy that partially regresses following cessation

Atrophy is well known to occur in the diaphragm and limb muscles of patients with chronic obstructive pulmonary disease (COPD), a disease predominantly caused by cigarette smoke exposure. Interestingly, non‐COPD smokers also exhibit limb muscle atrophy; a finding that implicates cigarette smoke as a cause of atrophy. This has been substantiated in animal models demonstrating that limb muscle atrophy occurs early following cigarette smoke exposure and prior to overt lung dysfunction. These studies also indicate that pro‐atrophy pathways are partially reversed upon the cessation of cigarette smoke exposure suggesting possible regression of atrophy. However, the effect of cigarette smoke exposure and cessation, on diaphragm muscle atrophy, has not been investigated. Thus, the overall objective of this project is to investigate the effect of cigarette smoke exposure on the development of diaphragm atrophy in mice. We hypothesize that cigarette smoke exposure in mice will induce diaphragm atrophy; further, will be reversed following cessation. Methods BALB/c mice were repeatedly exposed to room air or cigarette smoke twice a day, 5 days/week. To assess the pathological development of diaphragm atrophy, mice were exposed to either 8 or 24 weeks of cigarette smoke. Following initial exposure, a subset of mice were switched to room air for an additional 8 weeks to evaluate the effect of cigarette smoke cessation. All groups were compared to non‐smoking controls. At the time of sacrifice, mice were formalin fixed and diaphragm tissue was removed for histological evaluation of diaphragm myocyte cross sectional area (CSA). Results In comparison to non‐smoking controls, diaphragm CSA was reduced by 40% following 8 weeks cigarette smoke exposure and did not worsen by 24 weeks. Median diaphragm CSA in 8 and 24 week exposure groups were 220um 2 and 215um 2 respectively, which was significantly reduced from 370um 2 in non‐smoking controls (p<0.05). In mice switched to room air, diaphragm CSA was reduced by 20% as compared to non‐smoking controls; 298um 2 vs. 370um 2 respectively. Conclusions Here we demonstrate that diaphragm atrophy is induced early following cigarette smoke exposure and does not worsen with prolonged experience. Further, our data indicate that the cessation of cigarette smoke exposure partially regresses diaphragm atrophy. In future work we aim to identify the intracellular mechanisms through which diaphragm atrophy develops in response to cigarette smoke exposure. Support or Funding Information Canadian Thoracic Society/ Canadian Lung Association

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