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Identifying a New Mechanism of Sarcopenia by Autophagy

Sarcopenia is one of the critical factors in reducing Activity of Daily Life and associated with morbidity and mortality. Sarcopenia has also been linked to metabolic syndrome. In recent years, it has been reported that autophagy is one of the mechanisms as a cause of sarcopenia. Therefore, we focus...

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Autores principales: Yamada, Eijiro, Uehara, Ryota, Nakajima, Yasuyo, Horiguchi, Kazuhiko, Ishida, Emi, Matsumoto, Shunichi, Okada, Shunichi, Yamada, Masanobu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265700/
http://dx.doi.org/10.1210/jendso/bvab048.099
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author Yamada, Eijiro
Uehara, Ryota
Nakajima, Yasuyo
Horiguchi, Kazuhiko
Ishida, Emi
Matsumoto, Shunichi
Okada, Shunichi
Yamada, Masanobu
author_facet Yamada, Eijiro
Uehara, Ryota
Nakajima, Yasuyo
Horiguchi, Kazuhiko
Ishida, Emi
Matsumoto, Shunichi
Okada, Shunichi
Yamada, Masanobu
author_sort Yamada, Eijiro
collection PubMed
description Sarcopenia is one of the critical factors in reducing Activity of Daily Life and associated with morbidity and mortality. Sarcopenia has also been linked to metabolic syndrome. In recent years, it has been reported that autophagy is one of the mechanisms as a cause of sarcopenia. Therefore, we focused on autophagy as a system that can regulate both sarcopenia and metabolic syndrome in skeletal muscle and revealed that non-receptor tyrosine kinase Fyn not only participates in metabolic syndrome but also regulates autophagy regulating sarcopenia through STAT3 regulation, mainly using transgenic mice (Cell metabolism 2010, Cell Rep. 2012). However, since these were non-physiological studies, we proceeded with further studies and demonstrating that Fyn dependent STAT3 phosphorylation by IL6, which is involved in chronic inflammation and metabolic syndrome, was observed in mouse C2C12 myotube cells. Autophagy was decreased in those cells by both IL6 dependent and Fyn dependent mechanisms. Furthermore, in the denervated mouse model, not only both Fyn and IL6 gene expressions as well as the key muscle specific E3 ubiquitin ligases, Atrogin1 and MuRf1 were increased but the expression and phosphorylation levels of STAT3 were also augmented, while the autophagy activity was decreased. We believe that a denervated mouse model alone is not enough as a model for sarcopenia, thus we next introduced a hind limb suspension mouse model that promotes disuse atrophy by suspending the hind limb. Using this model, we found that muscle atrophy was observed mainly in the soleus muscle, tibialis anterior muscle, and the gastrocnemius muscle with Atrogin1 and MuRf1 increased. Increase of both IL6 and STAT3 expression/phosphorylation were also observed in the muscles of hind limb suspension mice. Autophagy activity, examined by intraperitoneal administration of colchicine, was decreased. These results strongly suggest that Fyn is involved not only in the metabolic syndrome but also in the pathogenesis of sarcopenia, and may lead to a better understanding of the pathology of sarcopenia obesity and the development of therapeutic methods.
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spelling pubmed-82657002021-07-09 Identifying a New Mechanism of Sarcopenia by Autophagy Yamada, Eijiro Uehara, Ryota Nakajima, Yasuyo Horiguchi, Kazuhiko Ishida, Emi Matsumoto, Shunichi Okada, Shunichi Yamada, Masanobu J Endocr Soc Adipose Tissue, Appetite, and Obesity Sarcopenia is one of the critical factors in reducing Activity of Daily Life and associated with morbidity and mortality. Sarcopenia has also been linked to metabolic syndrome. In recent years, it has been reported that autophagy is one of the mechanisms as a cause of sarcopenia. Therefore, we focused on autophagy as a system that can regulate both sarcopenia and metabolic syndrome in skeletal muscle and revealed that non-receptor tyrosine kinase Fyn not only participates in metabolic syndrome but also regulates autophagy regulating sarcopenia through STAT3 regulation, mainly using transgenic mice (Cell metabolism 2010, Cell Rep. 2012). However, since these were non-physiological studies, we proceeded with further studies and demonstrating that Fyn dependent STAT3 phosphorylation by IL6, which is involved in chronic inflammation and metabolic syndrome, was observed in mouse C2C12 myotube cells. Autophagy was decreased in those cells by both IL6 dependent and Fyn dependent mechanisms. Furthermore, in the denervated mouse model, not only both Fyn and IL6 gene expressions as well as the key muscle specific E3 ubiquitin ligases, Atrogin1 and MuRf1 were increased but the expression and phosphorylation levels of STAT3 were also augmented, while the autophagy activity was decreased. We believe that a denervated mouse model alone is not enough as a model for sarcopenia, thus we next introduced a hind limb suspension mouse model that promotes disuse atrophy by suspending the hind limb. Using this model, we found that muscle atrophy was observed mainly in the soleus muscle, tibialis anterior muscle, and the gastrocnemius muscle with Atrogin1 and MuRf1 increased. Increase of both IL6 and STAT3 expression/phosphorylation were also observed in the muscles of hind limb suspension mice. Autophagy activity, examined by intraperitoneal administration of colchicine, was decreased. These results strongly suggest that Fyn is involved not only in the metabolic syndrome but also in the pathogenesis of sarcopenia, and may lead to a better understanding of the pathology of sarcopenia obesity and the development of therapeutic methods. Oxford University Press 2021-05-03 /pmc/articles/PMC8265700/ http://dx.doi.org/10.1210/jendso/bvab048.099 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Adipose Tissue, Appetite, and Obesity
Yamada, Eijiro
Uehara, Ryota
Nakajima, Yasuyo
Horiguchi, Kazuhiko
Ishida, Emi
Matsumoto, Shunichi
Okada, Shunichi
Yamada, Masanobu
Identifying a New Mechanism of Sarcopenia by Autophagy
title Identifying a New Mechanism of Sarcopenia by Autophagy
title_full Identifying a New Mechanism of Sarcopenia by Autophagy
title_fullStr Identifying a New Mechanism of Sarcopenia by Autophagy
title_full_unstemmed Identifying a New Mechanism of Sarcopenia by Autophagy
title_short Identifying a New Mechanism of Sarcopenia by Autophagy
title_sort identifying a new mechanism of sarcopenia by autophagy
topic Adipose Tissue, Appetite, and Obesity
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265700/
http://dx.doi.org/10.1210/jendso/bvab048.099
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