Oxaliplatin induces cancer-like cachexia through distinct transcriptional pathways in mouse muscle and adipose depots

Cancer cachexia is a multifactorial, largely irreversible metabolic disorder characterized by skeletal muscle and adipose tissue depletion that is responsible for 20% of cancer-related deaths. Oxaliplatin, a platinum-based chemotherapeutic, is a common, first-line treatment for metastatic colorectal and other malignancies that result in cancer cachexia. Yet, it is unknown whether oxaliplatin contributes to these effects independently of cancer. To reveal its role in cachexia development, we administered a chronic human-equivalent oxaliplatin dose to non-tumor-bearing C57BL/6 mice. Daily activity, muscle wasting, fat depletion, and metabolic parameters were monitored through metabolic cages and echo-MRI measurements followed by postmortem muscle and fat tissue histology and bulk RNA seq. Our results show that a high accumulative oxaliplatin dose of 80 mg/kg leads to cachexia-like symptoms, characterized by severe loss of body mass, decreased food intake, diminished ambulatory activity accompanied by lowered core body temperature, decreased skeletal muscle mass, and loss of adipose tissue. RNA-seq data from muscle and adipose tissues indicate a complex mechanism that is in part driven by inflammation and adipokine activity. Comparison of oxaliplatin treatment with external human and murine datasets in cancer and fasting settings illustrates that while oxaliplatin shares many differentially expressed genes with these conditions, it also induces unique gene differentiation. These results suggested oxaliplatin alone induces a cachexia phenotype and thus may aggravate cancer-induced cachexia, highlighting the importance of early diagnostic and therapeutic interventions that target cachexia from both cancer and chemotherapy.