Abstract
Long-term cigarette smoke induces lung inflammatory injury and chronic obstructive pulmonary disease (COPD), associated with skeletal muscle inflammation. This study aimed at investigating how cigarette smoke promotes skeletal muscle inflammation and its molecular pathogenesis. Mice were exposed to air or cigarette smoke for 12 or 24 weeks, and C2C12 cells were stimulated with cigarette smoke extract (CSE). The mass and function, myotube formation, inflammatory cytokine production, histone deacetylase 2 (HDAC2) and nuclear factor-κB (NF-κB) p65 expression were detected in the gastrocnemius muscles of mice and C2C12 cells. In comparison with the control mice, cigarette smoke significantly damaged the lung and reduced the gastrocnemius muscle mass and body weights in mice. Cigarette smoke significantly down-regulated myosin heavy chain (MHC)-IIβ and HDAC2 expression, but enhanced NF-κBp65, keratinocyte chemoattractant (KC) and tumor necrosis factor (TNF)-α expression in the gastrocnemius muscles. CSE stimulation significantly inhibited the myotube formation, MyoD and HDAC2 expression, but enhanced NF-κBp65 expression, KC and TNF-α production in C2C12 cells, which were enhanced by HDAC2 knockdown and abrogated by a NF-κB inhibitor. CSE significantly inhibited the interaction of HDAC2 with NF-κBp65, and increased the levels of acetyl-NF-κBp65 in C2C12 cells. These data indicated that cigarette smoke inhibited HDAC2 expression and its interaction with NF-κBp65 to stimulate inflammation, contributing to the pathogenesis of COPD-related skeletal muscle atrophy in mice.
Highlights
Long term heavy cigarette smoke (CS) is risk for the development of chronic obstructive pulmonary disease (COPD)
We found that 12-24 weeks CS-exposure could reduced the gastrocnemius muscle mass and body weights in mice
CS reduced the relative levels of myosin heavy chain (MHC)-IIβ and histone deacetylase 2 (HDAC2) expression, enhanced the NFκBp65, keratinocyte chemoattractant (KC) and tumor necrosis factor (TNF)-α expression in the gastrocnemius muscles of mice
Summary
Long term heavy cigarette smoke (CS) is risk for the development of chronic obstructive pulmonary disease (COPD). Long-term CS induces inflammation, damages in the lung, result in extra-pulmonary comorbidities, such as skeletal muscle atrophy, coronary heart failure, depression, osteoporosis and obesity. A previous study has suggested that skeletal muscle atrophy is attributed to systemic inflammation mediated by the ‘‘spill-over’’ of inflammatory mediators into the circulation [5]. In patients with COPD, pro-inflammatory cytokines, like tumor necrosis factor (TNF)α, can activate the NF-κB signaling to increase inflammatory cytokine production and inducible nitric oxide synthase (iNOS) expression. These inflammatory mediators can facilitate the degradation of myosin heavy chain (MHC) through the ubiquitin-proteasome complex and muscle cell apoptosis. The mechanisms underlying the effect of long-term CS on the muscular morphology and mass, inflammation, the NF-κB activation, HDAC2 expression and activation have not been clarified in vivo
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