Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania.
Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
J Appl Physiol (1985). 2022 Dec 1;133(6):1273-1283. doi: 10.1152/japplphysiol.00247.2022. Epub 2022 Oct 6.
We investigated the impact of tumor burden on muscle wasting in metastatic (m) and xenograft (x) models of colorectal cancer (CRC). Male Nod SCID γ and CD2F1 mice were injected subcutaneously or intrasplenically with HCT116 or C26 tumor cells, respectively. CRC tumors resulted in significant muscle wasting regardless of tumor type or model, although muscle loss was exacerbated in mHCT116 hosts. The mHCT116 model decreased ribosomal (r)RNA content and rDNA transcription, whereas the mC26 model showed no loss of rRNA and the upregulation of rDNA transcription. The xHCT116 model reduced mTOR, RPS6, and 4E-BP1 phosphorylation, whereas the mHCT116 model had a similar effect on RPS6 and 4E-BP1 without altering mTOR phosphorylation. The C26 models caused a reduction in 4E-BP1 phosphorylation independent of mTOR. Muscle interleukin (IL)-6 mRNA was elevated in all models except xHCT116, and the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) mRNA was induced only in the mC26 model. IL-1β mRNA increased in all groups with greater expression in metastatic relative to the xenograft model regardless of tumor types. Our findings indicate that HCT116 tumor burden results in more drastic muscle wasting and anabolic deficits, whereas C26 tumor burden causes similar muscle wasting but exhibits a divergent proinflammatory phenotype. These results highlight potentially important divergence in the pathogenesis of muscle wasting among preclinical models of CRC and demonstrate that tumor burden plays a role in determining anabolic deficits and the expression of proinflammatory effectors of muscle wasting in a tumor-type-dependent manner. We provide evidence demonstrating that colorectal tumor burden plays a role in determining anabolic deficits and the expression of proinflammatory effectors of muscle wasting in a tumor-type-dependent manner.
我们研究了肿瘤负担对转移性（m）和异种移植（x）结直肠癌（CRC）模型中肌肉减少症的影响。雄性 Nod SCID γ和 CD2F1 小鼠分别皮下或脾内注射 HCT116 或 C26 肿瘤细胞。CRC 肿瘤导致肌肉明显减少，无论肿瘤类型或模型如何，尽管 mHCT116 宿主中的肌肉损失加剧。mHCT116 模型降低核糖体（r）RNA 含量和 rDNA 转录，而 mC26 模型则没有 rRNA 丢失并上调 rDNA 转录。xHCT116 模型降低了 mTOR、RPS6 和 4E-BP1 的磷酸化，而 mHCT116 模型对 RPS6 和 4E-BP1 的作用相似，而不改变 mTOR 磷酸化。C26 模型导致 mTOR 独立的 4E-BP1 磷酸化减少。除了 xHCT116，所有模型中的肌肉白细胞介素（IL）-6mRNA 都升高，而 NOD、LRR 和吡喃结构域包含蛋白 3（NLRP3）mRNA 仅在 mC26 模型中诱导。所有组的 IL-1β mRNA 增加，转移性肿瘤的表达高于异种移植模型。我们的研究结果表明，HCT116 肿瘤负担导致更严重的肌肉减少症和合成代谢缺陷，而 C26 肿瘤负担导致相似的肌肉减少症，但表现出不同的促炎表型。这些结果突出表明，在 CRC 的临床前模型中，肌肉减少症的发病机制可能存在重要差异，并表明肿瘤负担在以肿瘤类型依赖的方式决定合成代谢缺陷和肌肉减少症促炎效应物的表达方面发挥作用。我们提供的证据表明，结直肠肿瘤负担在以肿瘤类型依赖的方式决定肌肉减少症的合成代谢缺陷和促炎效应物的表达中起作用。
