Long-term cigarette smoke exposure inhibits histone deacetylase 2 expression and enhances the nuclear factor-κB activation in skeletal muscle of mice.

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.