RT Journal Article
SR Electronic
T1 Stage-specific muscle wasting mechanisms in a novel cancer cachexia mouse model for ovarian granulosa cell tumor
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.16.154385
DO 10.1101/2020.06.16.154385
A1 Yaqi Zhang
A1 Jie Zhu
A1 So-Youn Kim
A1 Megan M Romero
A1 Kelly A Even
A1 Takeshi Kurita
A1 Teresa K Woodruff
YR 2020
UL http://biorxiv.org/content/early/2020/06/17/2020.06.16.154385.abstract
AB Cachexia is a progressive muscle wasting syndrome that increases mortality risk in cancer patients, while there are still no effective treatment due to the complexity of syndrome and the lack of preclinical models. We identified a transgenic mice model with ovarian granulosa cell tumors mimic the progression of cachexia seen in humans, including drastic weight loss, skeletal muscle wasting and increased serum cachexia biomarker activin A and GDF15. Hypercatabolism was detected in skeletal muscle, having upregulation of E3 ligases Atrogin-1 and Murf-1. Our cachexia model exhibited stage-specific muscle wasting mechanisms. At precachexia stage, elevation of activin A activates p38 MAPK. Inhibition of activin A with Follistatin reversed weight loss at precachexia stage. At cachexia stage, energy stress in skeletal muscle activates AMPKα and leads to upregulation of FoxO3. Our results indicate this novel preclinical cancer cachexia model is exploitable for studying pathophysiological mechanisms and testing therapeutic agents of cachexia.Competing Interest StatementThe authors have declared no competing interest.