Campelj Dean G, Timpani Cara A, Spiesberger Guinevere, Formosa Luke E, Steele Joel R, Zhang Haijian, Schittenhelm Ralf B, Leow Lewis, Goodman Craig A, Rybalka Emma
Institute for Health and Sport, Victoria University, Melbourne, Victoria, Australia.
Biology of Ageing Laboratory, Centre for Healthy Ageing, Centenary Institute, Camperdown, New South Wales, Australia.
J Cachexia Sarcopenia Muscle. 2025 Jun;16(3):e13849. doi: 10.1002/jcsm.13849.
Anticancer chemotherapy is an underappreciated contributor to cancer cachexia, an often-irreversible body-wasting condition that causes 20%-30% of cancer-related deaths. An obstacle to predicting, monitoring and understanding the mechanisms underlying chemotherapy cachexia is that each cancer (and subtype) is assigned different chemotherapeutic compounds, typically in multiagent regimens. Here, we investigate the chemotherapy induction regimen (CIR) used in the haematological cancer, acute myeloid leukaemia (AML). We hypothesised that the AML CIR would induce cachexia, including loss of lean tissue mass and skeletal muscle atrophy.
Using an unbiased proteomics approach, we interrogated the underlying molecular mechanisms. Three-month-old male Balb/c mice were treated with the AML CIR via intraperitoneal injections of daunorubicin (1.7 mg/kg) on Days 1-3 and cytarabine (33.2 mg/kg) administered on Days 1-7 or vehicle. Mice were assessed 24 h after the last treatment, on Day 8, or allowed to recover for 2 weeks and assessed on Day 22. A third cohort was given access to running wheels in cages. We assessed body composition and whole-body metabolism and assessed the muscle proteome using quantitative tandem mass tag labelling LC-MS/MS analysis. Data are available via ProteomeXchange with identifier PXD063910.
The AML CIR-induced acute cachexia involved a ~10% loss of body mass, ~10% loss of lean mass and ~20% reduction in skeletal muscle fibre size. Whole-body metabolism and ambulatory activity declined. This cachexic phenotype did not recover over the 2-week post-CIR period (lean mass loss post-CIR: 1 week ~7% vs. 2 weeks ~9%). In voluntarily active CIR-treated mice, body wasting was exacerbated due to unchecked loss of fat mass (CIR sedentary: ~31% vs. CIR active: ~51%). Muscle proteome studies revealed upregulation of haptoglobin (Hp) and glutamine synthetase (Glul), which were positively correlated with body and lean mass loss. Hp was sensitive to the conditional induction, recovery and exacerbation of AML CIR-mediated cachexia, suggestive of biomarker potential.
The AML CIR induces an acute reduction of body, lean and fat mass underpinned by skeletal muscle atrophy, hypermetabolism and catabolism. Our data uncovered a conditionally sensitive muscle biomarker in Hp, which may be useful as a prognostic tool across other scenarios of chemotherapy-induced myopathy and cachexia or as a target for therapeutic discovery in follow-up studies.
抗癌化疗是癌症恶病质的一个未得到充分重视的促成因素，癌症恶病质是一种通常不可逆的身体消瘦状况，导致20%-30%的癌症相关死亡。预测、监测和理解化疗性恶病质潜在机制的一个障碍是，每种癌症（及其亚型）通常采用多药联合方案使用不同的化疗药物。在此，我们研究血液系统癌症急性髓系白血病（AML）中使用的化疗诱导方案（CIR）。我们假设AML的CIR会诱发恶病质，包括瘦组织质量的丧失和骨骼肌萎缩。
我们采用无偏倚蛋白质组学方法探究其潜在分子机制。3月龄雄性Balb/c小鼠在第1-3天通过腹腔注射柔红霉素（1.7mg/kg），并在第1-7天注射阿糖胞苷（33.2mg/kg）或赋形剂，接受AML的CIR治疗。在最后一次治疗后24小时（第8天）对小鼠进行评估，或者让小鼠恢复2周后在第22天进行评估。第三组小鼠可以使用笼子里的跑步轮。我们评估了身体组成和全身代谢，并使用定量串联质量标签标记液相色谱-质谱/质谱分析评估肌肉蛋白质组。数据可通过ProteomeXchange获得，标识符为PXD063910。
AML的CIR诱导的急性恶病质包括体重约10%的减轻、瘦体重约10%的减轻以及骨骼肌纤维大小约20%的减小。全身代谢和自主活动能力下降。这种恶病质表型在CIR后的2周内没有恢复（CIR后瘦体重减轻：1周约7%，2周约9%）。在自愿活动的接受CIR治疗的小鼠中，由于脂肪量不受控制的减少，身体消瘦加剧（CIR组久坐不动：约31%，CIR组活动：约51%）。肌肉蛋白质组研究显示触珠蛋白（Hp）和谷氨酰胺合成酶（Glul）上调，它们与体重和瘦体重减轻呈正相关。Hp对AML的CIR介导的恶病质的条件诱导、恢复和加重敏感，提示其具有作为生物标志物的潜力。
AML的CIR通过骨骼肌萎缩、代谢亢进和分解代谢导致身体、瘦体重和脂肪量急性减少。我们的数据揭示了一种对Hp有条件敏感的肌肉生物标志物，它可能作为化疗诱导的肌病和恶病质的其他情况的预后工具，或者作为后续研究中治疗发现的靶点。
