Cargando…
CHAC1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia
Muscle wasting is one of the main characteristics of cachexia associated with cancer and other chronic diseases and is often exacerbated by antineoplastic agents. Increased oxidative stress is associated with muscle wasting, along with depletion of glutathione, the most abundant endogenous antioxida...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10072464/ https://www.ncbi.nlm.nih.gov/pubmed/37014882 http://dx.doi.org/10.1371/journal.pone.0283806 |
_version_ | 1785019387005108224 |
---|---|
author | Li, Junjie Lu, Mingjian Ahn, Youngwook Cao, Kevin Pinkus, Cynthia A. Stansfield, John C. Wu, Zhidan Zhang, Bei B. |
author_facet | Li, Junjie Lu, Mingjian Ahn, Youngwook Cao, Kevin Pinkus, Cynthia A. Stansfield, John C. Wu, Zhidan Zhang, Bei B. |
author_sort | Li, Junjie |
collection | PubMed |
description | Muscle wasting is one of the main characteristics of cachexia associated with cancer and other chronic diseases and is often exacerbated by antineoplastic agents. Increased oxidative stress is associated with muscle wasting, along with depletion of glutathione, the most abundant endogenous antioxidant. Therefore, boosting endogenous glutathione has been proposed as a therapeutic strategy to prevent muscle wasting. Here, we tested this hypothesis by inactivating CHAC1, an intracellular glutathione degradation enzyme. We found CHAC1 expression is increased under multiple muscle wasting conditions in animal models, including fasting, cancer cachexia, and chemotherapy. The elevation of muscle Chac1 expression is associated with reduced glutathione level. CHAC1 inhibition via CRSPR/Cas9 mediated knock-in of an enzyme inactivating mutation demonstrates a novel strategy to preserve muscle glutathione levels under wasting conditions but fails to prevent muscle wasting in mice. These results suggest that preserving intracellular glutathione level alone may not be sufficient to prevent cancer or chemotherapy induced muscle wasting. |
format | Online Article Text |
id | pubmed-10072464 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-100724642023-04-05 CHAC1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia Li, Junjie Lu, Mingjian Ahn, Youngwook Cao, Kevin Pinkus, Cynthia A. Stansfield, John C. Wu, Zhidan Zhang, Bei B. PLoS One Research Article Muscle wasting is one of the main characteristics of cachexia associated with cancer and other chronic diseases and is often exacerbated by antineoplastic agents. Increased oxidative stress is associated with muscle wasting, along with depletion of glutathione, the most abundant endogenous antioxidant. Therefore, boosting endogenous glutathione has been proposed as a therapeutic strategy to prevent muscle wasting. Here, we tested this hypothesis by inactivating CHAC1, an intracellular glutathione degradation enzyme. We found CHAC1 expression is increased under multiple muscle wasting conditions in animal models, including fasting, cancer cachexia, and chemotherapy. The elevation of muscle Chac1 expression is associated with reduced glutathione level. CHAC1 inhibition via CRSPR/Cas9 mediated knock-in of an enzyme inactivating mutation demonstrates a novel strategy to preserve muscle glutathione levels under wasting conditions but fails to prevent muscle wasting in mice. These results suggest that preserving intracellular glutathione level alone may not be sufficient to prevent cancer or chemotherapy induced muscle wasting. Public Library of Science 2023-04-04 /pmc/articles/PMC10072464/ /pubmed/37014882 http://dx.doi.org/10.1371/journal.pone.0283806 Text en © 2023 Li et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Li, Junjie Lu, Mingjian Ahn, Youngwook Cao, Kevin Pinkus, Cynthia A. Stansfield, John C. Wu, Zhidan Zhang, Bei B. CHAC1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia |
title | CHAC1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia |
title_full | CHAC1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia |
title_fullStr | CHAC1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia |
title_full_unstemmed | CHAC1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia |
title_short | CHAC1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia |
title_sort | chac1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10072464/ https://www.ncbi.nlm.nih.gov/pubmed/37014882 http://dx.doi.org/10.1371/journal.pone.0283806 |
work_keys_str_mv | AT lijunjie chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia AT lumingjian chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia AT ahnyoungwook chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia AT caokevin chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia AT pinkuscynthiaa chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia AT stansfieldjohnc chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia AT wuzhidan chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia AT zhangbeib chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia |