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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0283806 |
| _version_ | 1797843182716715008 |
|---|---|
| author | Junjie Li Mingjian Lu Youngwook Ahn Kevin Cao Cynthia A Pinkus John C Stansfield Zhidan Wu Bei B Zhang |
| author_facet | Junjie Li Mingjian Lu Youngwook Ahn Kevin Cao Cynthia A Pinkus John C Stansfield Zhidan Wu Bei B Zhang |
| author_sort | Junjie Li |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-09T17:00:41Z |
| format | Article |
| id | doaj.art-7a45ed1fa2ee480283704deadb3cddbc |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-09T17:00:41Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-7a45ed1fa2ee480283704deadb3cddbc2023-04-21T05:32:37ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01184e028380610.1371/journal.pone.0283806CHAC1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia.Junjie LiMingjian LuYoungwook AhnKevin CaoCynthia A PinkusJohn C StansfieldZhidan WuBei B ZhangMuscle 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.https://doi.org/10.1371/journal.pone.0283806 |
| spellingShingle | Junjie Li Mingjian Lu Youngwook Ahn Kevin Cao Cynthia A Pinkus John C Stansfield Zhidan Wu Bei B Zhang CHAC1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia. PLoS ONE |
| 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 |
| url | https://doi.org/10.1371/journal.pone.0283806 |
| work_keys_str_mv | AT junjieli chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia AT mingjianlu chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia AT youngwookahn chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia AT kevincao chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia AT cynthiaapinkus chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia AT johncstansfield chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia AT zhidanwu chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia AT beibzhang chac1inactivationiseffectivetopreservemuscleglutathionebutisinsufficienttoprotectagainstmusclewastingincachexia |