Tang Kechun, Wagner Peter D, Breen Ellen C
Division of Physiology, Department of Medicine, University of California, San Diego, La Jolla, California 92093-0623, USA.
J Cell Physiol. 2010 Feb;222(2):320-7. doi: 10.1002/jcp.21955.
Skeletal muscle dysfunction contributes to exercise limitation in COPD. In this study cigarette smoke exposure was hypothesized to increase expression of the inflammatory cytokine, TNF-alpha, thereby suppressing PGC-1alpha, and hence affecting down stream molecules that regulate oxygen transport and muscle function. Furthermore, we hypothesized that highly vascularized oxidative skeletal muscle would be more susceptible to cigarette smoke than less well-vascularized glycolytic muscle. To test these hypotheses, mice were exposed to cigarette smoke daily for 8 or 16 weeks, resulting in 157% (8 weeks) and 174% (16 weeks) increases in serum TNF-alpha. Separately, TNF-alpha administered to C2C12 myoblasts was found to dose-dependently reduce PGC-1alpha mRNA. In the smoke-exposed mice, PGC-1alpha mRNA was decreased, by 48% in soleus and 23% in EDL. The vascular PGC-1alpha target molecule, VEGF, was also down-regulated, but only in the soleus, which exhibited capillary regression and an oxidative to glycolytic fiber type transition. The apoptosis PGC-1alpha target genes, atrogin-1 and MuRF1, were up-regulated, and to a greater extent in the soleus than EDL. Citrate synthase (soleus-19%, EDL-17%) and beta-hydroxyacyl CoA dehydrogenase (beta-HAD) (soleus-22%, EDL-19%) decreased similarly in both muscle types. There was loss of body and gastrocnemius complex mass, with rapid soleus but not EDL fatigue and diminished exercise endurance. These data suggest that in response to smoke exposure, TNF-alpha-mediated down-regulation of PGC-1alpha may be a key step leading to vascular and myocyte dysfunction, effects that are more evident in oxidative than glycolytic skeletal muscles.
骨骼肌功能障碍导致慢性阻塞性肺疾病（COPD）患者运动受限。在本研究中，假设香烟烟雾暴露会增加炎性细胞因子肿瘤坏死因子-α（TNF-α）的表达，从而抑制过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α），进而影响调节氧气运输和肌肉功能的下游分子。此外，我们假设血管丰富的氧化型骨骼肌比血管化程度较低的糖酵解型肌肉对香烟烟雾更敏感。为了验证这些假设，将小鼠每天暴露于香烟烟雾中8周或16周，导致血清TNF-α分别增加157%（8周）和174%（16周）。另外，发现给予C2C12成肌细胞TNF-α会剂量依赖性降低PGC-1α mRNA。在暴露于烟雾的小鼠中，PGC-1α mRNA减少，比目鱼肌减少48%，趾长伸肌（EDL）减少23%。血管PGC-1α靶分子血管内皮生长因子（VEGF）也下调，但仅在比目鱼肌中出现，该肌肉表现出毛细血管消退以及氧化型向糖酵解型纤维类型转变。凋亡相关PGC-1α靶基因atrogin-1和肌肉萎缩相关泛素连接酶1（MuRF1）上调，且在比目鱼肌中的上调程度大于EDL。两种肌肉类型中的柠檬酸合酶（比目鱼肌-19%，EDL-17%）和β-羟酰基辅酶A脱氢酶（β-HAD）（比目鱼肌-22%，EDL-19%）同样减少。出现体重和腓肠肌复合体质量减轻，比目鱼肌迅速疲劳而EDL未出现疲劳，运动耐力下降。这些数据表明，响应烟雾暴露时，TNF-α介导的PGC-1α下调可能是导致血管和心肌细胞功能障碍的关键步骤，这些影响在氧化型骨骼肌中比糖酵解型骨骼肌中更明显。
