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Myostatin is a novel tumoral factor that induces cancer cachexia

Humoral and tumoral factors collectively promote cancer-induced skeletal muscle wasting by increasing protein degradation. Although several humoral proteins, namely TNFα (tumour necrosis factor α) and IL (interleukin)-6, have been shown to induce skeletal muscle wasting, there is a lack of informati...

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Autores principales: Lokireddy, Sudarsanareddy, Wijesoma, Isuru Wijerupage, Bonala, Sabeera, Wei, Meng, Sze, Siu Kwan, McFarlane, Craig, Kambadur, Ravi, Sharma, Mridula
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408049/
https://www.ncbi.nlm.nih.gov/pubmed/22621320
http://dx.doi.org/10.1042/BJ20112024
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author Lokireddy, Sudarsanareddy
Wijesoma, Isuru Wijerupage
Bonala, Sabeera
Wei, Meng
Sze, Siu Kwan
McFarlane, Craig
Kambadur, Ravi
Sharma, Mridula
author_facet Lokireddy, Sudarsanareddy
Wijesoma, Isuru Wijerupage
Bonala, Sabeera
Wei, Meng
Sze, Siu Kwan
McFarlane, Craig
Kambadur, Ravi
Sharma, Mridula
author_sort Lokireddy, Sudarsanareddy
collection PubMed
description Humoral and tumoral factors collectively promote cancer-induced skeletal muscle wasting by increasing protein degradation. Although several humoral proteins, namely TNFα (tumour necrosis factor α) and IL (interleukin)-6, have been shown to induce skeletal muscle wasting, there is a lack of information regarding the tumoral factors that contribute to the atrophy of muscle during cancer cachexia. Therefore, in the present study, we have characterized the secretome of C26 colon cancer cells to identify the tumoral factors involved in cancer-induced skeletal muscle wasting. In the present study, we show that myostatin, a procachectic TGFβ (transforming growth factor β) superfamily member, is abundantly secreted by C26 cells. Consistent with myostatin signalling during cachexia, treating differentiated C2C12 myotubes with C26 CM (conditioned medium) resulted in myotubular atrophy due to the up-regulation of muscle-specific E3 ligases, atrogin-1 and MuRF1 (muscle RING-finger protein 1), and enhanced activity of the ubiquitin–proteasome pathway. Furthermore, the C26 CM also activated ActRIIB (activin receptor type II B)/Smad and NF-κB (nuclear factor κB) signalling, and reduced the activity of the IGF-I (insulin-like growth factor 1)/PI3K (phosphoinositide 3-kinase)/Akt pathway, three salient molecular features of myostatin action in skeletal muscles. Antagonists to myostatin prevented C26 CM-induced wasting in muscle cell cultures, further confirming that tumoral myostatin may be a key contributor in the pathogenesis of cancer cachexia. Finally, we show that treatment with C26 CM induced the autophagy–lysosome pathway and reduced the number of mitochondria in myotubes. These two previously unreported observations were recapitulated in skeletal muscles collected from C26 tumour-bearing mice.
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spelling pubmed-34080492012-08-06 Myostatin is a novel tumoral factor that induces cancer cachexia Lokireddy, Sudarsanareddy Wijesoma, Isuru Wijerupage Bonala, Sabeera Wei, Meng Sze, Siu Kwan McFarlane, Craig Kambadur, Ravi Sharma, Mridula Biochem J Research Article Humoral and tumoral factors collectively promote cancer-induced skeletal muscle wasting by increasing protein degradation. Although several humoral proteins, namely TNFα (tumour necrosis factor α) and IL (interleukin)-6, have been shown to induce skeletal muscle wasting, there is a lack of information regarding the tumoral factors that contribute to the atrophy of muscle during cancer cachexia. Therefore, in the present study, we have characterized the secretome of C26 colon cancer cells to identify the tumoral factors involved in cancer-induced skeletal muscle wasting. In the present study, we show that myostatin, a procachectic TGFβ (transforming growth factor β) superfamily member, is abundantly secreted by C26 cells. Consistent with myostatin signalling during cachexia, treating differentiated C2C12 myotubes with C26 CM (conditioned medium) resulted in myotubular atrophy due to the up-regulation of muscle-specific E3 ligases, atrogin-1 and MuRF1 (muscle RING-finger protein 1), and enhanced activity of the ubiquitin–proteasome pathway. Furthermore, the C26 CM also activated ActRIIB (activin receptor type II B)/Smad and NF-κB (nuclear factor κB) signalling, and reduced the activity of the IGF-I (insulin-like growth factor 1)/PI3K (phosphoinositide 3-kinase)/Akt pathway, three salient molecular features of myostatin action in skeletal muscles. Antagonists to myostatin prevented C26 CM-induced wasting in muscle cell cultures, further confirming that tumoral myostatin may be a key contributor in the pathogenesis of cancer cachexia. Finally, we show that treatment with C26 CM induced the autophagy–lysosome pathway and reduced the number of mitochondria in myotubes. These two previously unreported observations were recapitulated in skeletal muscles collected from C26 tumour-bearing mice. Portland Press Ltd. 2012-07-27 2012-08-15 /pmc/articles/PMC3408049/ /pubmed/22621320 http://dx.doi.org/10.1042/BJ20112024 Text en © 2012 The Author(s) The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by-nc/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Lokireddy, Sudarsanareddy
Wijesoma, Isuru Wijerupage
Bonala, Sabeera
Wei, Meng
Sze, Siu Kwan
McFarlane, Craig
Kambadur, Ravi
Sharma, Mridula
Myostatin is a novel tumoral factor that induces cancer cachexia
title Myostatin is a novel tumoral factor that induces cancer cachexia
title_full Myostatin is a novel tumoral factor that induces cancer cachexia
title_fullStr Myostatin is a novel tumoral factor that induces cancer cachexia
title_full_unstemmed Myostatin is a novel tumoral factor that induces cancer cachexia
title_short Myostatin is a novel tumoral factor that induces cancer cachexia
title_sort myostatin is a novel tumoral factor that induces cancer cachexia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408049/
https://www.ncbi.nlm.nih.gov/pubmed/22621320
http://dx.doi.org/10.1042/BJ20112024
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