Apelin Resistance Contributes to Muscle Loss during Cancer Cachexia in Mice

SIMPLE SUMMARY: Cancer cachexia is a highly debilitating syndrome involving severe body weight loss. Worldwide around 9–14.5 million cancer patients suffer from cachexia every year and many of them die because of cachexia. Our study aimed to assess the possible role of apelin against muscle loss during cancer growth given its beneficial effects against muscle atrophy during aging. We found apelin exhibiting advantageous effects against atrophy in in vitro models, but not in in vivo models, where we unraveled undesirable apelin resistance that may nullify apelin-based therapy for cancer cachexia. ABSTRACT: Cancer cachexia consists of dramatic body weight loss with rapid muscle depletion due to imbalanced protein homeostasis. We found that the mRNA levels of apelin decrease in muscles from cachectic hepatoma-bearing rats and three mouse models of cachexia. Furthermore, apelin expression inversely correlates with MuRF1 in muscle biopsies from cancer patients. To shed light on the possible role of apelin in cachexia in vivo, we generated apelin 13 carrying all the last 13 amino acids of apelin in D isomers, ultimately extending plasma stability. Notably, apelin D-peptides alter cAMP-based signaling in vitro as the L-peptides, supporting receptor binding. In vitro apelin 13 protects myotube diameter from dexamethasone-induced atrophy, restrains rates of degradation of long-lived proteins and MuRF1 expression, but fails to protect mice from atrophy. D-apelin 13 given intraperitoneally for 13 days in colon adenocarcinoma C26-bearing mice does not reduce catabolic pathways in muscles, as it does in vitro. Puzzlingly, the levels of circulating apelin seemingly deriving from cachexia-inducing tumors, increase in murine plasma during cachexia. Muscle electroporation of a plasmid expressing its receptor APJ, unlike apelin, preserves myofiber area from C26-induced atrophy, supporting apelin resistance in vivo. Altogether, we believe that during cachexia apelin resistance occurs, contributing to muscle wasting and nullifying any possible peptide-based treatment.