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). Use of ADT has been increasing in frequency and duration, such that side effects increasingly impact patient quality of life. One of the most significant side effects of ADT is sarcopenia, which leads to a loss of skeletal muscle mass and function, resulting in a clinical disability syndrome known as obese frailty. Using aged mice, we developed a mouse model of ADT-induced sarcopenia that closely resembles the phenotype seen in patients, including loss of skeletal muscle strength, reduced lean muscle mass, and increased adipose tissue. Sarcopenia onset occurred about 6 weeks after castration and was blocked by a soluble receptor (ActRIIB-Fc) that binds multiple TGFβ superfamily members, including myostatin, growth differentiation factor 11, 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, in 1 of 3 temporal patterns. Specifically, activin A and activin AB levels increase and decline before onset of strength loss at 6 weeks after castration, and myostatin levels increase coincident with the onset of strength loss and then decline. In contrast, activin B and growth differentiation factor 11 levels increase after the onset of strength loss, 8-10 weeks after castration. The observed patterns of ligand induction may represent differential contributions 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.
Department of Cancer Genetics (C.P., S.S., J.J.K., K.L.N.) and Center for Personalized Medicine (J.J.K.), Roswell Park Cancer Institute; Buffalo, New York 14263; and James P. Wilmot Cancer Center and Department of Medicine (D.M.S.), Department of Orthopedics and Center for Musculoskeletal Research (J.V.C.), and Department of Pathology and Laboratory Medicine (K.L.N.), University of Rochester, School of Medicine and Dentistry, Rochester, New York 14642.
Chunliu
C
Pan
Department of Cancer Genetics (C.P., S.S., J.J.K., K.L.N.) and Center for Personalized Medicine (J.J.K.), Roswell Park Cancer Institute; Buffalo, New York 14263; and James P. Wilmot Cancer Center and Department of Medicine (D.M.S.), Department of Orthopedics and Center for Musculoskeletal Research (J.V.C.), and Department of Pathology and Laboratory Medicine (K.L.N.), University of Rochester, School of Medicine and Dentistry, Rochester, New York 14642.
Shalini
S
Singh
Department of Cancer Genetics (C.P., S.S., J.J.K., K.L.N.) and Center for Personalized Medicine (J.J.K.), Roswell Park Cancer Institute; Buffalo, New York 14263; and James P. Wilmot Cancer Center and Department of Medicine (D.M.S.), Department of Orthopedics and Center for Musculoskeletal Research (J.V.C.), and Department of Pathology and Laboratory Medicine (K.L.N.), University of Rochester, School of Medicine and Dentistry, Rochester, New York 14642.
Deepak M
DM
Sahasrabudhe
Department of Cancer Genetics (C.P., S.S., J.J.K., K.L.N.) and Center for Personalized Medicine (J.J.K.), Roswell Park Cancer Institute; Buffalo, New York 14263; and James P. Wilmot Cancer Center and Department of Medicine (D.M.S.), Department of Orthopedics and Center for Musculoskeletal Research (J.V.C.), and Department of Pathology and Laboratory Medicine (K.L.N.), University of Rochester, School of Medicine and Dentistry, Rochester, New York 14642.
Joe V
JV
Chakkalakal
Department of Cancer Genetics (C.P., S.S., J.J.K., K.L.N.) and Center for Personalized Medicine (J.J.K.), Roswell Park Cancer Institute; Buffalo, New York 14263; and James P. Wilmot Cancer Center and Department of Medicine (D.M.S.), Department of Orthopedics and Center for Musculoskeletal Research (J.V.C.), and Department of Pathology and Laboratory Medicine (K.L.N.), University of Rochester, School of Medicine and Dentistry, Rochester, New York 14642.
John J
JJ
Krolewski
Department of Cancer Genetics (C.P., S.S., J.J.K., K.L.N.) and Center for Personalized Medicine (J.J.K.), Roswell Park Cancer Institute; Buffalo, New York 14263; and James P. Wilmot Cancer Center and Department of Medicine (D.M.S.), Department of Orthopedics and Center for Musculoskeletal Research (J.V.C.), and Department of Pathology and Laboratory Medicine (K.L.N.), University of Rochester, School of Medicine and Dentistry, Rochester, New York 14642.
Kent L
KL
Nastiuk
D030301:Activin Receptors, Type II / Q000378:metabolism; D028341:Activins / Q000378:metabolism; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002369:Castration / Q000009:adverse effects*; D055412:Growth Differentiation Factors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053580:Muscle Strength / Q000235:genetics / Q000502:physiology; D055435:Myostatin / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D055948:Sarcopenia / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; C119153:Gdf11 protein, mouse; D055412:Growth Differentiation Factors; D055435:Myostatin; D016212:Transforming Growth Factor beta; C422405:activin A; C044147:activin B; D028341:Activins; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B