TGFβ Superfamily Members Mediate Androgen Deprivation Therapy-Induced Obese Frailty in Male Mice

First line treatment for recurrent and metastatic prostate cancer is androgen deprivation therapy (ADT).UseofADThasbeenincreasing infrequencyandduration, such that side effects increasingly impact patient quality of life. One of the most significant side effects of ADT is sarcopenia, which leads toaloss of skeletalmusclemassandfunction, resulting inaclinical disabilitysyndromeknown as obese frailty. Utilizingagedmice,wedeveloped amousemodelof ADT-induced sarcopenia that closely resembles the phenotype seen in patients, including loss of skeletal muscle strength, a reducedleanmusclemass,andincreasedadiposetissue.Sarcopeniaonsetoccurredaboutsixweeks after castration and was blocked by a soluble receptor (ActRIIB-Fc) that binds multiple TGFß su- perfamily members, including myostatin, GDF11, activin A, activin B, and activin AB. Analysis of ligand expression in both gastrocnemius and triceps brachii muscles demonstrates that each of these proteins is induced in response to ADT, inoneof three temporal patterns. Specifically, activin A and activin AB levels increase and decline prior to onset of strength loss at six weeks post- castration, and myostatin levels increase coincident with the onset of strength loss and then de- cline. In contrast, activin B and GDF-11 levels increase after the onset of strength loss, 8–10 weeks post-castration. The observed patterns of ligand induction may represent differential contribu- tions to the development and/or maintenance of sarcopenia. We hypothesize that some or all of these ligands are targets for therapy to ameliorate ADT-induced sarcopenia in prostate cancer patients.