Internal Medicine Research Unit, World Research, Development and Medical, Pfizer, Inc., Cambridge, Massachusetts, United States of America.
Emerging Science & Innovation, World Research, Development and Medical, Pfizer, Inc., Cambridge, Massachusetts, United States of America.
PLoS One. 2023 Apr 4;18(4):e0283806. doi: 10.1371/journal.pone.0283806. eCollection 2023.
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.
肌肉减少症是与癌症和其他慢性疾病相关的恶病质的主要特征之一，并且经常被抗肿瘤药物加剧。氧化应激的增加与肌肉减少症有关，同时还伴随着谷胱甘肽的耗竭，谷胱甘肽是最丰富的内源性抗氧化剂。因此，提高内源性谷胱甘肽已被提议作为一种预防肌肉减少症的治疗策略。在这里，我们通过使细胞内谷胱甘肽降解酶 CHAC1 失活来检验这一假设。我们发现 CHAC1 的表达在动物模型中的多种肌肉减少症情况下增加，包括禁食、癌症恶病质和化疗。肌肉 Chac1 表达的升高与谷胱甘肽水平降低有关。通过 CRSPR/Cas9 介导的酶失活突变的基因敲入来抑制 CHAC1，证明了在消耗条件下保持肌肉谷胱甘肽水平的新策略，但不能预防小鼠的肌肉减少症。这些结果表明，单独保持细胞内谷胱甘肽水平可能不足以预防癌症或化疗引起的肌肉减少症。
