Apsana Lamsal, Benedikte Andersen Sonja, Unni Nonstad, Jayne Kurganovs Natalie, Je Skipworth Richard, Geir Bjørkøy, Kristine Pettersen
Department of Biomedical Laboratory Science, Faculty of Natural Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
Cancer Metab. 2025 Jun 5;13(1):27. doi: 10.1186/s40170-025-00396-0.
Despite decades of efforts to find successful treatment approaches, cachexia remains a major unmet medical need. This condition, that affects patients with diverse underlying conditions, is characterized by severe muscle loss and is associated with reduced quality of life and limited survival. Search for underlying mechanisms that may guide cachexia treatment has mainly evolved around potential atrophy-inducing roles of inflammatory mediators, and in cancer patients, tumor-derived factors. Recently, a new paradigm emerged as it is becoming evident that specific immune cells inhabit atrophic muscle tissue. Arginase 1 (Arg1) expression is characteristic of these immune cells. Studies of potential contributions of these immune cells to loss of muscle mass and function is in its infancy, and the contribution of ARG1 to these processes remains elusive.
Analyses of RNA sequencing data from murine cachexia models and comprehensive, unbiased open approach proteomics analyses of skeletal myotubes was performed. In vitro techniques were employed to evaluate mitochondrial function and capacity in skeletal muscle cells and cardiomyocytes. Functional bioassays were used to measure autophagy activity. ARG1 level in patients' plasma was evaluated using ELISA, and the association between ARG1 level and patient survival, across multiple types of cancer, was examined using the online database Kaplan-Meier plotter.
In line with arginine-degrading activity of ARG1, we found signs of arginine restriction in atrophic muscles. In response to arginine restriction, mitochondrial functions and ATP generation was severely compromised in both skeletal muscle cells and in cardiomyocytes. In skeletal muscle cells, arginine restriction enhanced the expression of autophagic proteins, suggesting autophagic degradation of cellular content. Reduction in mitochondria marker TIMM23 supports selective autophagic degradation of mitochondria (mitophagy). In arginine starved cardiomyocytes, mitochondrial dysfunction is accompanied by both increased bulk autophagy and mitophagy. In cancer patients, we found an association between ARG1 expression and accelerated weight loss and reduced survival, further supporting a role of ARG1-producing cells in cachexia pathogenesis.
Together, our findings point to a mechanism for cachexia which depends on expansion of ARG1-expressing myeloid cells, local restriction of arginine, loss of mitochondrial capacity and induced catabolism in skeletal muscle cells and in the heart.
尽管数十年来一直在努力寻找成功的治疗方法，但恶病质仍然是一个尚未得到满足的主要医学需求。这种疾病影响着患有各种潜在疾病的患者，其特征是严重的肌肉流失，并与生活质量下降和生存期有限相关。寻找可能指导恶病质治疗的潜在机制主要围绕炎症介质以及癌症患者中肿瘤衍生因子的潜在萎缩诱导作用展开。最近，一种新的范式出现了，因为越来越明显的是，特定的免疫细胞存在于萎缩的肌肉组织中。精氨酸酶1（Arg1）的表达是这些免疫细胞的特征。对这些免疫细胞对肌肉质量和功能丧失的潜在贡献的研究尚处于起步阶段，而ARG1对这些过程的贡献仍然难以捉摸。
对来自小鼠恶病质模型的RNA测序数据进行分析，并对骨骼肌肌管进行全面、无偏倚的开放方法蛋白质组学分析。采用体外技术评估骨骼肌细胞和心肌细胞的线粒体功能和能力。使用功能生物测定法测量自噬活性。使用酶联免疫吸附测定（ELISA）评估患者血浆中的ARG1水平，并使用在线数据库Kaplan-Meier plotter检查多种癌症类型中ARG1水平与患者生存率之间的关联。
与ARG1的精氨酸降解活性一致，我们在萎缩肌肉中发现了精氨酸受限的迹象。作为对精氨酸限制的反应，骨骼肌细胞和心肌细胞中的线粒体功能和ATP生成均受到严重损害。在骨骼肌细胞中，精氨酸限制增强了自噬蛋白的表达，表明细胞内容物的自噬降解。线粒体标志物TIMM23的减少支持线粒体的选择性自噬降解（线粒体自噬）。在精氨酸饥饿的心肌细胞中，线粒体功能障碍伴随着大量自噬和线粒体自噬的增加。在癌症患者中，我们发现ARG1表达与体重加速减轻和生存期缩短之间存在关联，进一步支持了产生ARG1的细胞在恶病质发病机制中的作用。
总之，我们的研究结果指出了一种恶病质机制,该机制取决于表达ARG1的髓样细胞的扩增、精氨酸的局部限制、线粒体能力的丧失以及骨骼肌细胞和心脏中诱导的分解代谢。
