Supraphysiologic Administration of GDF11 Induces Cachexia in Part by Upregulating GDF15

Summary The age-related effects of GDF11have been a subject of controversy. Here, we find that elevated GDF11causes signs of cachexiain mice: reduced food intake, body weight, and muscle mass. GDF11also elicited a significant elevation in plasma Activin A, previously shown to contribute to the loss of skeletal muscle. The effects of GDF11on skeletal muscle could be reversed by administration of antibodies to the Activin type II receptors. In addition to the effects on muscle, GDF11increased plasma GDF15, an anorecticagent. The anorexia, but not the muscle loss, could be reversed with a GDF15- neutralizing antibody. GDF15upregulation is due to GDF11-induced recruitment of SMAD2/3 to the GDF15promoter. Inhibition of GDF15can restore appetite but cannot restore the GDF11-induced loss of muscle mass, which requires blockade of ActRII signaling. These findings are relevant for treatment of cachexia.