Nontargeted Metabolomics Reveals Altered Fatty Acid, Glucose, and Arginine Metabolism in Cancer Cachexia

Abstract

Cancer cachexia is a metabolic and wasting disease that occurs in up to 80% of cancer patients. Currently, there are no clear diagnostic criteria, its effects are irreversible, and it cannot be treated. Most patients progress undetected to late stages of cancer cachexia, stop responding to traditional treatment, and die without hope for intervention. As such, there is a great need for accurate biomarkers. To determine the metabolic signature of cancer cachexia in muscle to assist with metabolic biomarker discovery, heart and gastrocnemius tissues from 15‐week‐old male ApcMin mice (Apc+) and litter‐matched non‐carrier mice (WT) were analyzed by non‐targeted GC/MS metabolomics. Analysis identified 136 metabolites in the hearts of cachectic (Apc+) mice with 3 metabolites significantly (P<0.05) decrease compared to WT mice: campesterol, hypoxanthine, and alanine. Variable Importance in Projection (VIP) analysis, which shows which metabolites contributes most significantly to group, and pathway analysis revealed that linoleic acid metabolism; biosynthesis of unsaturated fatty acids; arginine metabolism; taurine/hypotaurine metabolism; and arginine biosynthesis pathways were affected by cancer cachexia. Analysis also identified 135 metabolites in the gastrocnemius of cachectic (Apc+) mice with 4 significant (P<0.05) metabolites: 1,5‐anhydroglucitol and fumaric acid were decreased, lysine and ribose‐5‐phospate were increased. VIP analysis and pathway analysis showed linoleic acid metabolism; biosynthesis of unsaturated fatty acids; taurine/hypotaurine metabolism; glycolysis/gluconeogenesis metabolism; and arginine biosynthesis pathways were affected by cancer cachexia. Taken together, these data demonstrate altered fatty acid metabolism, arginine metabolism, glycolysis, taurine metabolism, and proline metabolism in hearts and skeletal muscle of cachectic mice. Interestingly, skeletal muscle shows an increase in fatty acid metabolism and decrease in glucose and 1,5‐anhydroglucitol while the heart shows an opposite response. Differently, cachectic hearts showed an increase in glycolytic metabolites compared to skeletal muscle. This indicates a non‐preferential fuel switch in the heart towards less energetically favorable glycolysis (vs fatty acid metabolism). Additionally, cachectic heart exhibited decreased levels of taurine and campesterol which have been shown to be cardioprotective. Finally, both the heart and skeletal muscle shows an increase in proline metabolism which has been shown to be upregulated during times of metabolic stress and arginine metabolism which plays a key role in inhibiting protein metabolism and promoting proteolysis. These data shed important light on the metabolic derangement associated with cancer cachexia that in turn lead to muscle and fat wasting. Such data may provide a valuable stepping stone in understanding the metabolic consequence of cancer cachexia as well as the identification of metabolic biomarkers.