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.