PDF(Pubmed)
Abstract：
Cigarette smoking (CS) causes skeletal muscle dysfunction, leading to sarcopenia and worse prognosis of patients with diverse systemic diseases. Here, we found that CS exposure prevented C2C12 myoblasts proliferation in a dose-dependent manner. Immunoblotting assays verified that CS exposure promoted the expression of cell cycle suppressor protein p21. Furthermore, CS exposure significantly inhibited replication-dependent (RD) histone transcription and caused S phase arrest in the cell cycle during C2C12 proliferation. Mechanistically, CS deregulated the expression levels of Nuclear Protein Ataxia-Telangiectasia Locus (NPAT/p220). Notably, the proteasome inhibitor MG132 was able to reverse the expression of NPAT in myoblasts, implying that the degradation of CS-mediated NPAT is proteasome-dependent. Overexpression of NPAT also rescued the defective proliferation phenotype induced by CS in C2C12 myoblasts. Taken together, we suggest that CS exposure induces NPAT degradation in C2C12 myoblasts and impairs myogenic proliferation through NPAT associated proteasomal-dependent mechanisms. As an application of the proteasome inhibitor MG132 or overexpression of NPAT could reverse the impaired proliferation of myoblasts induced by CS, the recovery of myoblast proliferation may be potential strategies to treat CS-related skeletal muscle dysfunction.
摘要：
吸烟（CS）会导致骨骼肌功能障碍，导致肌肉减少症，各种系统性疾病患者的预后较差。这里,我们发现CS暴露以剂量依赖的方式阻止C2C12成肌细胞增殖。免疫印迹试验证实CS暴露促进细胞周期抑制蛋白p21的表达。此外，CS暴露显着抑制复制依赖性（RD）组蛋白转录，并在C2C12增殖过程中引起细胞周期的S期停滞。机械上,CS下调核蛋白共济失调-毛细血管扩张基因座(NPAT/p220)的表达水平。值得注意的是,蛋白酶体抑制剂MG132能够逆转NPAT在成肌细胞中的表达，这意味着CS介导的NPAT的降解是蛋白酶体依赖性的。NPAT的过表达也挽救了C2C12成肌细胞中CS诱导的有缺陷的增殖表型。一起来看,我们建议CS暴露诱导C2C12成肌细胞中的NPAT降解，并通过NPAT相关的蛋白酶体依赖性机制损害成肌增殖。作为蛋白酶体抑制剂MG132的应用或NPAT的过表达可以逆转CS诱导的成肌细胞增殖受损,恢复成肌细胞增殖可能是治疗CS相关骨骼肌功能障碍的潜在策略.
