Background and Aims: Cancer cachexia is a complex syndrome affecting most cancer patients and is directly responsible for about 20% of cancer-related deaths. Previous studies showed muscle proteolysis hyper-activation and mitophagy induction in tumor-bearing animals. While basal mitophagy is required for maintaining muscle mass and quality, excessive mitophagy promotes uncontrolled protein degradation, muscle loss and impaired function. BNIP3, a key mitophagy-related protein, is significantly increased in the muscles of both mice and human cancer hosts. This study aimed to define the potential of mitigating mitophagy via BNIP3 downregulation in preserving mitochondrial integrity, counteracting skeletal muscle loss in experimental cancer cachexia. Methods: Two in vivo gene delivery methods were performed to knock down muscle BNIP3: electroporation of a BNIP3-specific shRNA expression vector or adenovirus injection. Results: The electroporation effectively reduced muscle BNIP3 in healthy mice but was ineffective in C26 tumor-bearing mice. In contrast, adenovirus-mediated BNIP3 knockdown successfully decreased BNIP3 levels also in tumor hosts. Although BNIP3 knockdown did not impact overall on body or muscle mass, it improved muscle fiber size in C26-bearing miceh2, suggesting partial prevention of muscle atrophy. Mitochondrial respiratory chain complexes (OxPhos) and TOM20 protein levels were consistently rescued, indicating improvements in mitochondrial mass, while H2O2levels were unchanged among the groups, suggesting that BNIP3 downregulation does not impair the endogenous control of oxidative balance. Conclusions: These findings suggest that a fine balance between mitochondrial disposal and biogenesis is fundamental for preserving muscle homeostasis and highlight a potential role for BNIP3 modulation against cancer-induced muscle wasting.
背景与目的：癌症恶病质是一种影响多数癌症患者的复杂综合征，直接导致约20%的癌症相关死亡。先前研究表明，荷瘤动物存在肌肉蛋白分解过度激活和线粒体自噬诱导现象。基础线粒体自噬对维持肌肉质量和功能至关重要，但过度自噬会引发不可控的蛋白降解、肌肉流失及功能损伤。BNIP3作为关键线粒体自噬相关蛋白，在小鼠及人类癌症宿主的肌肉组织中显著升高。本研究旨在探讨通过下调BNIP3抑制线粒体自噬对维持线粒体完整性、对抗实验性癌症恶病质中骨骼肌流失的潜在作用。方法：采用两种体内基因递送方法敲低肌肉BNIP3表达：电转染BNIP3特异性shRNA表达载体或腺病毒注射。结果：电转染能有效降低健康小鼠肌肉BNIP3，但对C26荷瘤小鼠无效；而腺病毒介导的BNIP3敲低在荷瘤宿主中同样成功降低BNIP3水平。尽管BNIP3敲低未显著影响总体体重或肌肉质量，但改善了C26荷瘤小鼠的肌纤维横截面积，提示其对肌肉萎缩具有部分预防作用。线粒体呼吸链复合物（OxPhos）和TOM20蛋白水平均得到稳定恢复，表明线粒体质量改善；各组间H2O2水平无显著变化，说明BNIP3下调未损害氧化平衡的内源性调控。结论：这些发现提示线粒体清除与生物合成间的精细平衡对维持肌肉稳态至关重要，并揭示了BNIP3调控在对抗癌症诱导肌肉消耗中的潜在作用。
BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia
肿瘤(癌症)患者之家