Exercise Protects Against Cancer-Induced Gastrocnemius Metabolic Alterations

Abstract

Cancer cachexia is a complex metabolic wasting disease. Currently, there are no clear diagnostic criteria, its effects are irreversible, and it cannot be treated. However, exercise has been shown to be beneficial for wasting disorders. PURPOSE: To determine how cancer cachexia alters muscle 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, gastrocnemius tissues were analyzed for metabolite signatures via non-targeted GC/MS metabolomics. RESULTS: Analysis identified 135 metabolites in the gastrocnemius of cachectic (SED + Apc) mice with 3 metabolites significantly (P < 0.05) increased compared to SED + WT mice: hydroxyproline, ornithine, and lysine. One metabolite was significantly (P < .01) decreased in SED + Apc compared to SED + WT mice: 1-5-1-5-anhydroglucitol. Variable Importance in Projection (VIP) analysis and pathway analysis revealed that the urea cycle, Warburg metabolism, inositol phosphate metabolism, and arginine and proline biosynthesis were affected by cancer cachexia. Following exercise, Ex+Apc gastrocnemius ornithine and hydroxyproline were significantly decreased (P < 0.01) compared to SED + Apc. Conversely, Ex+Apc gastrocnemius 1-5-anhydroglucitol was significantly (P < 0.01) increased compared to SED + Apc. CONCLUSION: These data indicate that cancer cachexia significantly disrupts arginine and proline metabolism, inositol phosphate metabolism, and the urea cycle in cachectic skeletal muscle. Interestingly, aerobic exercise appears to abolish many metabolic perturbations imposed by cancer cachexia. Hydroxyproline (elevated in SED + Apc) has been shown to be increased during times of metabolic stress, however exercise reversed this signal. 1-5-anhydroglucitol (decreased in SED + Apc) is a marker of glycemic control and was restored to basal levels with exercise. Such data may provide a valuable steppingstone in understanding the metabolic consequence of cancer cachexia as well as the identification of metabolic biomarkers. Furthermore, these data shed important light on the mechanisms of the benefits of exercise in cancer survivors.