Human breast cancer xenograft model implicates peroxisome proliferator-activated receptor signaling as driver of cancer-induced muscle fatigue

Purpose: This study tested the hypothesis that a patient-derived orthotopic xenograft (PDOX) model would recapitulate the common clinical phenomenon of breast cancer (BC)-induced skeletal muscle (SkM) fatigue in the absence of muscle wasting. This study additionally sought to identify drivers of this condition to facilitate the development of therapeutic agents for BC patients experiencing muscle fatigue. Experimental Design: Eight female BC-PDOX-bearing mice were produced via transplantation of tumor tissue from eight female BC patients. Individual hind limb muscles from BC-PDOX mice were isolated at euthanasia for RNA-sequencing, gene and protein analyses, and an ex vivo muscle contraction protocol to quantify tumor-induced aberrations in SkM function. Differentially expressed genes (DEGs) in the BC-PDOX mice relative to control mice were identified using DESeq2, and multiple bioinformatics platforms were employed to contextualize the DEGs. Results: We found that SkM from BC-PDOX-bearing mice showed greater fatigability than control mice, despite no differences in absolute muscle mass. PPAR, mTOR, IL-6, IL-1, and several other signaling pathways were implicated in the transcriptional changes observed in the BC-PDOX SkM. Moreover, three independent in silico analyses identified PPAR signaling as highly dysregulated in the SkM of both BC-PDOX-bearing mice and early stage non-metastatic human BC patients. Conclusions: Collectively, these data demonstrate that the BC-PDOX model recapitulates the expected BC-induced SkM fatigue and further identify aberrant PPAR signaling as an integral factor in the pathology of this condition.

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