CHAC1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia

• Published in: PloS one Vol. 18; no. 4; p. e0283806
• Main Authors: Li, Junjie, Lu, Mingjian, Ahn, Youngwook, Cao, Kevin, Pinkus, Cynthia A, Stansfield, John C, Wu, Zhidan, Zhang, Bei B
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04-04-2023; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Antineoplastic drugs; Antioxidants; Atrophy; Autophagy; Biology and Life Sciences; Cachexia; Cachexia - metabolism; Cachexia - prevention & control; Cancer; Care and treatment; Chemotherapy; Chronic illnesses; Chronic obstructive pulmonary disease; Colorectal cancer; Deactivation; Depletion; Enzymes; Fasting; Fibrosarcoma; gamma-Glutamylcyclotransferase - metabolism; Genomes; Glutathione; Glutathione - metabolism; Health aspects; Hypotheses; Inactivation; Intracellular; Lipid peroxidation; Lung cancer; Medicine and Health Sciences; Mice; Muscle, Skeletal - metabolism; Muscles; Muscular Atrophy - pathology; Musculoskeletal system; Mutation; Neoplasms - complications; Neoplasms - drug therapy; Neoplasms - metabolism; Ovarian cancer; Oxidative stress; Pancreatic cancer; Patient outcomes; Proteins; Tumors; United States
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0283806

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.