Stage-dependent effects of cancer cachexia on myocardial ischemia-reperfusion injury in mice
Q YeAbstract
Introduction
Cancer is a major comorbidity that may worsen outcomes after myocardial ischemia-reperfusion (IR) injury. Cancer-associated cachexia (CAC) is an anabolic wasting syndrome characterized by muscle atrophy and systemic metabolic alterations, but its stage-dependent impact on IR remains unclear, particularly across different stages of cachexia progression.
Methods
Male Balb/c mice were injected subcutaneously with 1×10^6 C26 colon carcinoma cells or C26-shIL-6 cells to induce and distinguish either early (day 8–9) or advanced (day 18–20) stages of CAC. And non–tumor-bearing mice served as controls. Myocardial IR injury was induced (n=16) by left anterior descending coronary artery ligation for 40 minutes followed by 72 hours reperfusion. Cardiac function was assessed by echocardiography, and the extent of myocardial injury assessed by plasma troponin levels. Cardiac tissue proteomics was assessed using unbiased mass spectrometry–based analysis, while pSTAT3 expression was examined by western blotting and mitochondrial respiration was additionally assessed prior to IR insult.
Results
Cachexia was confirmed a significant fat and lean mass loss (p < 0.0001) in our model. Interestingly, the expression of pSTAT3 was markedly increased in cardiac tissue from advanced stage of CAC mice. In addition, gene ontology analysis was identified a massive deregulation of oxidative phosphorylation proteins expression in CAC mice heart tissue. In line with, the capacity of FA metabolism was declined in the same group in compared to non-tumor or C26-shIL-6 group. Furthermore, the markers for autophagy was significantly and exclusively upregulated in heart tissue from CAC (advanced-stage) mice. Functionally, LVEF was moderately reduced in CAC vs. non–tumor mice before IR, but post-IR decline was attenuated in CAC mice, accompanied by lower cTnI and infarct size. In advanced CAC, LVEF decreased from baseline to pre-IR (p = 0.0019) and post-IR (p = 0.0197). While PBS controls showed significant pre- vs. post-IR reduction (p = 0.0009). For cTnI, PBS (p = 0.0313) and advanced CAC (p = 0.0349) showed significant increases post-IR.
Conclusion
Our findings highlight a stage-dependent effects of CAC in respect to myocardial IR injury. While early cachexia may contribute to systemic frailty, advanced CAC appears to induce adaptive mechanisms, including enhanced pTAT3 levels, metabolic rewiring (shifting to glicolyis), and activation of autophagy, which collectively and synergistic manner render to myocardium paradoxically more resistant to IR-injury. Ongoing proteomic and mechanistic studies will further clarify molecular pathways and may identify novel therapeutic targets for cardioprotection in setting of acute IR-injury.cardiac function resultspSTAT3 results