Angiotensin-II-induced Muscle Wasting is Mediated by 25-Hydroxycholesterol via GSK3β Signaling Pathway.
While angiotensin II (ang II) has been implicated in the pathogenesis of cardiac cachexia (CC), the molecules that mediate ang II's wasting effect have not been identified. It is known TNF-α level is increased in patients with CC, and TNF-α release is triggered by ang II. We therefore hypothesized that ang II induced muscle wasting is mediated by TNF-α. Ang II infusion led to skeletal muscle wasting in wild type (WT) but not in TNF alpha type 1 receptor knockout (TNFR1KO) mice, suggesting that ang II induced muscle loss is mediated by TNF-α through its type 1 receptor. Microarray analysis identified cholesterol 25-hydroxylase (Ch25h) as the down stream target of TNF-α. Intraperitoneal injection of 25-hydroxycholesterol (25-OHC), the product of Ch25h, resulted in muscle loss in C57BL/6 mice, accompanied by increased expression of atrogin-1, MuRF1 and suppression of IGF-1/Akt signaling pathway. The identification of 25-OHC as an inducer of muscle wasting has implications for the development of specific treatment strategies in preventing muscle loss.
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China.
Congcong
C
Shen
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, PR China. Electronic address: 13913506369@163.com.
Jin
J
Zhou
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China.
Xiaoxiao
X
Wang
Guangdong Cardiovascular Institute, Guangzhou Medical University, Guangzhou, Guangdong, PR China.
Xi-Yong
XY
Yu
Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, No. 415, Fengyang Road, Shanghai, PR China.
Chun
C
Liang
Cardiovascular Disease Center, The First Hospital of Ji Lin University, Changchun, Jilin 130021, PR China.
Bin
B
Liu
Department of Cardiac Surgery, Fuwai Hospital, PR China.
Xiangbin
X
Pan
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China.
Qiong
Q
Zhao
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China.
Jenny Lee
JL
Song
Department of Gynecology, The Affiliated Maternity and Child Health Hospital of Nanjing Medical University, Wuxi, PR China.
Jiajun
J
Wang
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China.
Meiyu
M
Bao
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China.
Chaofan
C
Wu
The Department of Cardiovascular Surgery of the First Affiliated Hospital and the Institute for Cardiovascular Science, Soochow University, Suzhou, Jiangsu 215123, PR China. Electronic address: yangxin_li@yahoo.com.
Yangxin
Y
Li
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China. Electronic address: yaohua_song1@yahoo.com.
Yao-Hua
YH
Song
D000804:Angiotensin II; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D020869:Gene Expression Profiling / Q000379:methods; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006888:Hydroxycholesterols; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D006888:Hydroxycholesterols; D009124:Muscle Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D013830:Thiadiazoles; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D007334:Insulin-Like Growth Factor I; C007997:25-hydroxycholesterol; D013250:Steroid Hydroxylases; C507384:cholesterol 25-hydroxylase; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt
Angiotensin II; Cardiac cachexia; Ch25h; Heart failure; TNF-α