Endurance Exercise Abolishes Cancer‐Mediated Cardiac Dysfunction and Metabolic Alterations

Abstract

Cancer remains one of the leading causes of death worldwide. Of those battling cancer, up to 80% will develop cancer cachexia, a devastating metabolic wasting disease, that leads to poor treatment responses and markedly decreased survival. At the present, its effects are not fully reversible and it there is no standard treatment strategy. However, exercise has been shown to be beneficial for wasting disorders. PURPOSE: To determine how cancer cachexia alters cardiac function and metabolism, and whether aerobic exercise can protect against cancer-cachexia mediated alterations. METHODS: Male ApcMin mice (Apc) and litter-matched non-carrier mice (WT) underwent a 10-week voluntary wheel run (Ex) exercise regimen or remained sedentary (SED). At 15 weeks, cardiac tissues were analyzed for metabolite signatures via non-targeted GC/MS metabolomics. Cardiac function was assessed by echocardiography. RESULTS: Echocardiography revealed cancer significantly decreased fractional shortening (FS; P<0.05, SED+Apc vs all other groups), while exercise increased FS (P<0.05, Ex+Apc vs all other groups). Non-targeted metabolomics identified 136 metabolites in the heart of cachectic (SED+Apc) mice with 5 metabolites significantly (P<0.05) decreased compared to SED+WT mice: taurine, hypotaurine, O-phosphocolamine, ribose-5-phosphate, and campesterol. One metabolite was significantly (P<0.01) increased in SED+Apc compared to SED+WT mice: proline. Variable Importance in Projection (VIP) analysis and pathway analysis revealed that the taurine metabolism, arginine and proline metabolism, and urea cycle were affected by cancer cachexia. Interestingly, Ex+Apc hearts exhibited significantly (P<0.05) increased taurine, hypotaurine, O-phosphocolamine, ribose-5-phosphate, and campesterol compared to Sed+Apc. Conversely, Ex+Apc hearts exhibited significantly (P<0.05) decreased proline compared to SED+Apc.CONCLUSION: These data indicate that cancer cachexia causes cardiac dysfunction and disrupts cardiac taurine, proline, and arginine metabolism in the cachectic heart. Interestingly, aerobic exercise appears to abolish many metabolic perturbations imposed by cancer cachexia. Taurine has been shown to play an important role in the respiratory chain, hypotaurine has been shown to be myoprotective, and campesterol has been shown to be an indicator of low cardiometabolic risk. Such data may provide a valuable insight in understanding the metabolic consequence of cancer cachexia-mediated cardiac dysfunction as well as identify possible metabolic biomarkers. Furthermore, these data shed important light on the mechanisms of the benefits of exercise in cancer survivors.