Background/Objectives: Breast cancer (BC) is the second most commonly diagnosed cancer worldwide and is accompanied by fatigue during both active disease and remission in the majority of cases. Our lab has measured fatigue in isolated muscles from treatment-naive BC patient-derived orthotopic xenograft (BC-PDOX) mice. Here, we conducted a preclinical trial of pioglitazone in BC-PDOX mice to determine its efficacy in ameliorating BC-induced muscle fatigue, as well as its effects on transcriptomic, metabolomic, and lipidomic profiles in skeletal muscle.Methods: The pioglitazone and vehicle groups were treated orally for 4 weeks upon reaching a tumor volume of 600 mm3. Whole-animal indirect calorimetry was used to evaluate systemic metabolic states. The transcriptome was profiled using short-read bulk RNA sequencing (RNA-seq). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to profile the metabolome and lipidome. Fast and slow skeletal muscle function were evaluated using isolated ex vivo testing.Results: Pioglitazone was associated with a 16.634% lower average O2consumption (mL∙h−1,p= 0.035), 16.309% lower average CO2production (mL∙h−1,p= 0.022), and 16.4% lower cumulative energy expenditure (EE) (kcal∙h−1,p= 0.035), with no changes in substrate utilization. RNA-seq supported the downstream effects of pioglitazone on target genes and displayed considerable upregulation of mitochondrial bioenergetic pathways. K-means cluster 5 showed enrichment of the PPAR signaling pathway (adj. p< 0.05, Log2FC = 2.58). Skeletal muscle metabolomic and lipidomic profiles exhibited dysregulation in response to BC, which was partially restored in pioglitazone-treated mice compared to vehicle-treated BC-PDOX mice. In particular, the overall abundance of total ceramide levels was significantly lower in the PioTx group (−46.327%,p= 0.048). Despite molecular support for pioglitazone’s efficacy, isolated muscle function was not affected by pioglitazone treatment. No significant difference in the area under the fatigue curve (AUC) was found between the pioglitazone and vehicle groups (p= 0.596).Conclusions: BC induces multi-omic dysregulation in skeletal muscle, which pioglitazone partially ameliorates. Future research should focus on profiling systemic metabolic dysfunction, identifying molecular biomarkers of fatigue, and testing alternative pioglitazone treatment regimens.
背景/目的：乳腺癌是全球第二大常见癌症，多数患者在疾病活动期及缓解期均伴有疲劳症状。本实验室已在未经治疗的乳腺癌患者来源原位移植瘤模型小鼠的离体肌肉中检测到疲劳现象。本研究通过开展吡格列酮在BC-PDOX小鼠中的临床前试验，旨在评估其改善乳腺癌诱导肌肉疲劳的疗效，并探究其对骨骼肌转录组、代谢组和脂质组的影响。 方法：当肿瘤体积达到600 mm³时，将吡格列酮组和载体对照组进行为期4周的口服给药。采用全动物间接热量测定法评估全身代谢状态。通过短读长批量RNA测序技术分析转录组特征，利用液相色谱-串联质谱法进行代谢组和脂质组分析。采用离体外功能测试评估快慢骨骼肌功能。 结果：吡格列酮干预使平均耗氧量降低16.634%（mL·h⁻¹，p=0.035），平均二氧化碳生成量降低16.309%（mL·h⁻¹，p=0.022），累计能量消耗降低16.4%（kcal·h⁻¹，p=0.035），且未改变底物利用率。RNA测序结果证实吡格列酮对靶基因的下游调控作用，并显示线粒体生物能量通路显著上调。K均值聚类第5组显示PPAR信号通路富集（校正p<0.05，Log2FC=2.58）。骨骼肌代谢组和脂质组在乳腺癌影响下呈现失调状态，而吡格列酮治疗组较载体对照组部分恢复该失调。特别值得注意的是，吡格列酮治疗组总神经酰胺水平整体丰度显著降低（-46.327%，p=0.048）。尽管分子层面证据支持吡格列酮的疗效，但离体肌肉功能未受治疗影响。疲劳曲线下面积在两组间无显著差异（p=0.596）。 结论：乳腺癌可诱导骨骼肌多组学失调，吡格列酮能部分改善该现象。未来研究应聚焦于系统代谢功能障碍的特征分析、疲劳分子生物标志物的鉴定以及探索替代性吡格列酮治疗方案。
肿瘤(癌症)患者之家