Most prostate cancers depend on androgens for growth, and therefore, the mainstay treatment for advanced, recurrent, or metastatic prostate cancer is androgen deprivation therapy (ADT). A prominent side effect in patients receiving ADT is an obese frailty syndrome that includes fat gain and sarcopenia, defined as the loss of muscle function accompanied by reduced muscle mass or quality. Mice bearing Pten-deficient prostate cancers were examined to gain mechanistic insight into ADT-induced sarcopenic obesity. Castration induced fat gain as well as skeletal muscle mass and strength loss. Catabolic TGF-β family myokine protein levels were increased immediately prior to strength loss, and pan-myokine blockade using a soluble receptor (ActRIIB-Fc) completely reversed the castration-induced sarcopenia. The onset of castration-induced strength and muscle mass loss, as well as the increase in catabolic TGF-β family myokine protein levels, were coordinately accelerated in tumor-bearing mice relative to tumor-free mice. Notably, growth differentiation factor 11 (GDF11) increased in muscle after castration only in tumor-bearing mice, but not in tumor‑free mice. An early surge of GDF11 in prostate tumor tissue and in the circulation suggests that endocrine GDF11 signaling from tumor to muscle is a major driver of the accelerated ADT-induced sarcopenic phenotype. In tumor-bearing mice, GDF11 blockade largely prevented castration-induced strength loss but did not preserve muscle mass, which confirms a primary role for GDF11 in muscle function and suggests an additional role for the other catabolic myokines.
Chunliu Pan, Neha Jaiswal Agrawal, Yanni Zulia, Shalini Singh, Kai Sha, James L. Mohler, Kevin H. Eng, Joe V. Chakkalakal, John J. Krolewski, Kent L. Nastiuk
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