Abstract
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.
Highlights
While many men diagnosed with prostate cancer (PrCa) are cured with local therapy, the principal treatment for PrCa control in patients who present with more advanced disease, are medically unfit for local therapy, or have recurrent PrCa is androgen deprivation therapy (ADT) [1]
We previously reported that ADT-induced sarcopenia in normal mice closely resembles the obese frailty phenotype seen in patients [16]
In this report we examined an autochthonous PrCa (PB-Cre4 Ptenfl/fl) mouse model for castration-induced sarcopenia to better understand the mechanism of ADT-induced sarcopenia in patients with PrCa
Summary
While many men diagnosed with prostate cancer (PrCa) are cured with local therapy, the principal treatment for PrCa control in patients who present with more advanced disease, are medically unfit for local therapy, or have recurrent PrCa is androgen deprivation therapy (ADT) [1]. ADT-induced sarcopenia is accompanied by fat gain, and both increase with the duration of ADT [7]. Adiposity increases fat infiltration into muscle, thereby reducing muscle quality and further degrading muscle function [8, 9]. The loss of muscle mass but not fat mass differentiates ADT-induced sarcopenia from tumor cachexia, which is marked by loss of mass in both compartments [10]. Despite frequent overall weight gain resulting from adiposity in men receiving ADT, these men lose strength, resulting in functional deficits, including an increased risk of falls and fractures [11]. ADT-induced sarcopenia is most likely the underlying mechanism accounting for an “obese frailty” syndrome described in men receiving ADT for PrCa [12]. A combination of exercise and testosterone therapy can reverse frailty in many populations, but these interventions are problematic for many patients with PrCa [13,14,15]
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