PDF(Pubmed)
Abstract：
Skeletal muscle aging and sarcopenia result in similar changes in the levels of aging markers. However, few studies have examined cancer sarcopenia from the perspective of aging. Therefore, this study investigated aging in cancer sarcopenia and explored its causes in vitro and in vivo. In mouse aging, in vitro cachexia, and mouse cachexia models, skeletal muscles showed similar changes in aging markers including oxidative stress, fibrosis, reduced muscle differentiation potential, and telomere shortening. Furthermore, examination of mitochondrial DNA from skeletal muscle revealed a 5 kb deletion in the major arc; truncation of complexes I, IV, and V in the electron transport chain; and reduced oxidative phosphorylation (OXPHOS). The mouse cachexia model demonstrated high levels of high-mobility group box-1 (HMGB1) and tumor necrosis factor-α (TNFα) in cancer ascites. Continuous administration of neutralizing antibodies against HMGB1 and TNFα in this model reduced oxidative stress and abrogated mitochondrial DNA deletion. These results suggest that in cancer sarcopenia, mitochondrial oxidative stress caused by inflammatory cytokines leads to mitochondrial DNA damage, which in turn leads to decreased OXPHOS and the promotion of aging.
摘要：
骨骼肌衰老和肌肉减少症导致衰老标志物水平的相似变化。然而,很少有研究从衰老的角度研究癌症肌肉减少症。因此,这项研究调查了癌症肌肉减少症的衰老，并探讨了其在体外和体内的原因。在小鼠衰老中，体外恶病质，和老鼠恶病质模型，骨骼肌在衰老标志物包括氧化应激方面表现出相似的变化，纤维化，肌肉分化潜能降低，端粒缩短。此外，对骨骼肌线粒体DNA的检查显示主弧有5kb的缺失；复合物I的截断，IV,和电子传输链中的V;和减少的氧化磷酸化(OXPHOS)。小鼠恶病质模型显示癌性腹水中高水平的高迁移率组box-1（HMGB1）和肿瘤坏死因子-α（TNFα）。在该模型中连续施用抗HMGB1和TNFα的中和抗体减少了氧化应激并消除了线粒体DNA缺失。这些结果表明，在癌症中，炎症细胞因子引起的线粒体氧化应激导致线粒体DNA损伤,这反过来导致OXPHOS降低和促进衰老。
