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Stage-specific muscle wasting mechanisms in a novel cancer cachexia mouse model for ovarian granulosa cell tumor

By Yaqi Zhang, Jie Zhu, So-Youn Kim, Megan M Romero, Kelly A Even, Takeshi Kurita, Teresa K Woodruff

Posted 17 Jun 2020
bioRxiv DOI: 10.1101/2020.06.16.154385

Cachexia is a progressive muscle wasting syndrome that increases morbidity and mortality risk in patients with cancer. However, the molecular mechanisms underlying the development of muscle wasting in cancer cachexia are still unclear due to the complexity of the syndrome and the lack of preclinical models. Here we demonstrate that transgenic mice with spontaneous ovarian granulosa cell tumors, generated by constitutive activation of phosphatidylinositol-4,5-bisphosphate 3-kinase in oocytes, mimic the progression of cachexia seen in humans, including drastic weight loss, skeletal muscle wasting, liver cell apoptosis, and depletion of the inner epithelial layer of the stomach. Hypercatabolism was detected in skeletal muscle, having overactivation of proteolytic activity and autophagy through upregulation of expression of the muscle-specific ubiquitin E3 ligases Atrogin-1 and Murf-1 as well as lysosomal autophagy marker Lc3. Serum levels of two biomarkers of cachexia, activin A and GDF15, increased significantly before weight loss and were maintained at consistently high levels during cachexia progression. Our cachexia mouse model exhibited a complex set of stage-specific muscle wasting mechanisms. The p38 MAPK pathway was highly activated in skeletal muscle in early-stage cachexia (precachexia, <5% weight loss), concurrent with an elevation in activin A. In mice with advanced cachexia (cachectic, 10%-15% weight loss), the p38 MARK signaling decreased to baseline. Inhibition of activin A with Fst288 injection reversed weight loss to a greater extent at the precachexia stage than at cachectic stage. Upregulation of Atrogin-1, Murf-1, and LC3a transcription, as well as their shared upstream transcriptional regulator FoxO3, strongly correlated with weight loss. At cachectic stages, AMPK╬▒ signaling was activated in energy-depleted skeletal muscle, leading to upregulation of FoxO3 gene transcription. 18F-FDG PET/CT revealed higher tumor glucose consumption in mice with cachectic mice compared with precachexia mice. Our novel preclinical model of cancer-related cachexia will allow further studies of the initiation and development of cachexia, the underlying pathophysiological mechanisms, and potential therapeutic agents. ### Competing Interest Statement The authors have declared no competing interest.

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