Haptoglobin and Glutamine Synthetase May Biomark Cachexia Induced by Antiacute Myeloid Leukaemia Chemotherapy

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.