Integrative Muscle Biology Laboratory, Exercise Science Department, Columbia, SC, USA.
Skelet Muscle. 2012 Jul 6;2:14. doi: 10.1186/2044-5040-2-14.
Muscle protein turnover regulation during cancer cachexia is being rapidly defined, and skeletal muscle mitochondria function appears coupled to processes regulating muscle wasting. Skeletal muscle oxidative capacity and the expression of proteins regulating mitochondrial biogenesis and dynamics are disrupted in severely cachectic ApcMin/+ mice. It has not been determined if these changes occur at the onset of cachexia and are necessary for the progression of muscle wasting. Exercise and anti-cytokine therapies have proven effective in preventing cachexia development in tumor bearing mice, while their effect on mitochondrial content, biogenesis and dynamics is not well understood. The purposes of this study were to 1) determine IL-6 regulation on mitochondrial remodeling/dysfunction during the progression of cancer cachexia and 2) to determine if exercise training can attenuate mitochondrial dysfunction and the induction of proteolytic pathways during IL-6 induced cancer cachexia.
ApcMin/+ mice were examined during the progression of cachexia, after systemic interleukin (IL)-6r antibody treatment, or after IL-6 over-expression with or without exercise. Direct effects of IL-6 on mitochondrial remodeling were examined in cultured C2C12 myoblasts.
Mitochondrial content was not reduced during the initial development of cachexia, while muscle PGC-1α and fusion (Mfn1, Mfn2) protein expression was repressed. With progressive weight loss mitochondrial content decreased, PGC-1α and fusion proteins were further suppressed, and fission protein (FIS1) was induced. IL-6 receptor antibody administration after the onset of cachexia improved mitochondrial content, PGC-1α, Mfn1/Mfn2 and FIS1 protein expression. IL-6 over-expression in pre-cachectic mice accelerated body weight loss and muscle wasting, without reducing mitochondrial content, while PGC-1α and Mfn1/Mfn2 protein expression was suppressed and FIS1 protein expression induced. Exercise normalized these IL-6 induced effects. C2C12 myotubes administered IL-6 had increased FIS1 protein expression, increased oxidative stress, and reduced PGC-1α gene expression without altered mitochondrial protein expression.
Altered expression of proteins regulating mitochondrial biogenesis and fusion are early events in the initiation of cachexia regulated by IL-6, which precede the loss of muscle mitochondrial content. Furthermore, IL-6 induced mitochondrial remodeling and proteolysis can be rescued with moderate exercise training even in the presence of high circulating IL-6 levels.
癌症恶病质期间肌肉蛋白质周转率的调节正在迅速明确，骨骼肌线粒体功能似乎与调节肌肉消耗的过程相关。在严重恶病质的 ApcMin/+ 小鼠中，骨骼肌氧化能力和调节线粒体生物发生和动力学的蛋白质表达受到破坏。尚未确定这些变化是否在恶病质开始时发生，以及它们是否是肌肉消耗进展的必要条件。运动和抗细胞因子疗法已被证明可有效预防荷瘤小鼠恶病质的发展，但其对线粒体含量、生物发生和动力学的影响尚不清楚。本研究的目的是 1）确定白细胞介素-6（IL-6）在癌症恶病质进展过程中对线粒体重塑/功能障碍的调节，2）确定运动训练是否可以减轻 IL-6 诱导的癌症恶病质期间的线粒体功能障碍和蛋白水解途径的诱导。
在恶病质进展过程中、全身白细胞介素（IL）-6r 抗体治疗后或 IL-6 过表达时加上或不加上运动，检查 ApcMin/+ 小鼠。在培养的 C2C12 成肌细胞中检查 IL-6 对线粒体重塑的直接影响。
在恶病质的初始发展过程中，线粒体含量没有减少，而肌肉 PGC-1α 和融合（Mfn1、Mfn2）蛋白表达受到抑制。随着体重的逐渐减轻，线粒体含量下降，PGC-1α 和融合蛋白进一步受到抑制，而分裂蛋白（FIS1）被诱导。恶病质开始后给予 IL-6 受体抗体可改善线粒体含量、PGC-1α、Mfn1/Mfn2 和 FIS1 蛋白表达。在预恶病质小鼠中过表达 IL-6 加速了体重减轻和肌肉消耗，而不减少线粒体含量，同时抑制 PGC-1α 和 Mfn1/Mfn2 蛋白表达并诱导 FIS1 蛋白表达。运动使这些 IL-6 诱导的作用正常化。给予 IL-6 的 C2C12 肌管中 FIS1 蛋白表达增加，氧化应激增加，PGC-1α 基因表达减少，而线粒体蛋白表达不变。
调节线粒体生物发生和融合的蛋白质表达是 IL-6 调节的恶病质起始的早期事件，发生在肌肉线粒体含量丧失之前。此外，即使在循环中存在高 IL-6 水平的情况下，中等强度的运动训练也可以挽救 IL-6 诱导的线粒体重塑和蛋白水解。
