Abstract：
Cigarette smoke (CS) is the major risk factor for chronic obstructive pulmonary disease (COPD), and sarcopenia is one of the significant comorbidities of COPD. However, the pathogenesis of CS-related deficient skeletal muscle regeneration has yet to be clarified. The impact of CS on myoblast differentiation was examined, and then we determined which HDAC influenced the myogenic process and muscle atrophy in vitro and in vivo. Finally, we further investigated the potential mechanisms via RNA sequencing. Long-term CS exposure activated skeletal muscle primary satellite cells (SCs) while inhibiting differentiation, and defective myogenesis was also observed in C2C12 cells treated with CS extract (CSE). The level of HDAC9 changed in vitro and in vivo in CS exposure models as well as COPD patients, as detected by bioinformatics analysis. Our data showed that CSE impaired myogenic capacity and myotube formation in C2C12 cells via HDAC9. Moreover, inhibition of HDAC9 in mice exposed to CS prevented skeletal muscle dysfunction and promoted SC differentiation. The results of RNA-Seq analysis and verification indicated that HDAC9 knockout improved muscle differentiation in CS-exposed mice, probably by acting on the AKT/mTOR pathway and inhibiting the P53/P21 pathway. More importantly, the serum of HDAC9 KO mice exposed to CS alleviated the differentiation impairment of C2C12 cells caused by serum intervention in CS-exposed mice, and this effect was inhibited by LY294002 (an AKT/mTOR pathway inhibitor). These results suggest that HDAC9 plays an essential role in the defective regeneration induced by chronic exposure to CS.
摘要：
香烟烟雾（CS）是慢性阻塞性肺疾病（COPD）的主要危险因素，肌少症是COPD的重要合并症之一。然而,CS相关骨骼肌再生不足的发病机制尚待阐明。检查了CS对成肌细胞分化的影响，然后我们确定了HDAC在体外和体内影响肌源性过程和肌肉萎缩。最后,我们通过RNA测序进一步研究了潜在的机制.长期CS暴露激活骨骼肌原代SCs，同时抑制分化，在用CS提取物(CSE)处理的C2C12细胞中也观察到有缺陷的肌生成。在CS暴露模型和COPD患者中，HDAC9水平在体外和体内发生变化，通过生物信息学分析检测到。我们的数据显示CSE通过HDAC9损害了C2C12细胞中的肌源性能力和肌管形成。此外，在暴露于CS的小鼠中抑制HDAC9可预防骨骼肌功能障碍并促进SC分化。RNA-Seq分析和验证结果表明，HDAC9敲除可改善CS暴露小鼠的肌肉分化，可能通过作用于AKT/mTOR通路和抑制P53/P21通路。更重要的是,CS暴露HDAC9KO小鼠的血清减轻了CS暴露小鼠血清干预引起的C2C12细胞分化障碍，LY294002（AKT/mTOR通路抑制剂）抑制了这种作用。这些结果表明，HDAC9在慢性暴露于CS引起的缺陷再生中起着至关重要的作用。
