TNF-alpha-mediated reduction in PGC-1alpha may impair skeletal muscle function after cigarette smoke exposure.
TNF-alpha-mediated reduction in PGC-1alpha may impair skeletal muscle function after cigarette smoke exposure.
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DOI：
10.1002/jcp.21955
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发表时间：
2010-03
影响因子：
5.6
通讯作者：
Breen EC
中科院分区：
文献类型：
--
作者：
Tang K;Wagner PD;Breen EC
骨骼肌功能障碍导致COPD患者运动受限。在这项研究中，香烟烟雾暴露被假设增加炎症细胞因子、TNF-α和调节氧运输和肌肉功能的下游分子的表达。此外，我们假设，与血管化程度较低的糖酵解肌肉相比，血管化程度高的氧化骨骼肌更容易受到香烟烟雾的损害。为了验证这些假设，小鼠在8周和16周内每天暴露于香烟烟雾中，导致血清TNF-α增加157%（8周）和174%（16周）。另外，给药于C2C12成肌细胞的TNF-α可剂量依赖性地降低PGC-1α mRNA。血管PGC-1α靶分子VEGF也下调，但仅在比目鱼中下调，表现为毛细血管萎缩和氧化向糖酵解纤维型转变。与EDL相比，PGC-1α靶基因atrogin-1和MuRF1在比目鱼中表达上调，且上调幅度更大。柠檬酸合成酶（比目鱼- 19%，EDL - 17%）和β-羟酰基辅酶a脱氢酶（β-HAD）（比目鱼- 22%，EDL - 19%）在两种肌肉类型中均有相似的下降。有身体和腓肠肌复合体的损失，有快速比目鱼肌，但没有EDL疲劳和运动耐力下降。这些数据表明，在烟雾暴露的反应中，TNF-α介导的PGC-1α下调可能是导致血管和肌细胞功能障碍的关键步骤，其作用在氧化骨骼肌中比糖酵解骨骼肌更明显。
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-α, and down stream molecules that regulate oxygen transport and muscle function. Furthermore, we hypothesized that highly-vascularized oxidative skeletal muscles would be more susceptible to the damaging effects of cigarette smoke compared to a less well-vascularized glycolytic muscle. To test these hypotheses mice were exposed to daily periods of cigarette smoke over 8 and 16-weeks resulting in 157% (8 wks) and 174% (16 wks) increases in serum TNF-α. Separately TNF-α administered to C2C12 myoblasts was found to dose dependently reduce PGC-1α mRNA. The vascular PGC-1α 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-1α target genes, atrogin-1 and MuRF1, were upregulated and to a greater extent in the soleus compared to the EDL. Citrate synthase (soleus −19%, EDL −17%) and β-hydroxyacyl CoA dehydrogenase (β-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-α mediated down-regulation of PGC-1α may be a key step leading to vascular and myocyte dysfunction, effects that are more evident in oxidative than glycolytic skeletal muscles.
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影响因子：
--
作者：
MRAZKOVA, O;GRIM, M;CARLSON, BM
通讯作者：
CARLSON, BM
影响因子：
10
作者：
Schols, AMWJ;Buurman, WA;Wouters, EFM
通讯作者：
Wouters, EFM
DOI：
10.1097/00008483-199811000-00005
发表时间：
1998-11-01
期刊：
Journal of cardiopulmonary rehabilitation
影响因子：
--
作者：
Jobin, J;Maltais, F;Simard, C
通讯作者：
Simard, C
影响因子：
5.5
作者：
Adhihetty, Peter J.;Uguccioni, Giulia;Hood, David A.
通讯作者：
Hood, David A.
影响因子：
4.8
作者：
Handschin, Christoph;Chin, Sherry;Spiegelman, Bruce M.
通讯作者：
Spiegelman, Bruce M.