Prostate tumor–derived GDF11 accelerates androgen deprivation therapy–induced sarcopenia
Chunliu Pan, … , John J. Krolewski, Kent L. Nastiuk
Chunliu Pan, … , John J. Krolewski, Kent L. Nastiuk
Published February 20, 2020
Citation Information: JCI Insight. 2020;5(6):e127018. https://doi.org/10.1172/jci.insight.127018.
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Research Article Muscle biology Oncology

Prostate tumor–derived GDF11 accelerates androgen deprivation therapy–induced sarcopenia

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.

Authors

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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Figure 3

Castration increased active catabolic TGF-β family myokine proteins in skeletal muscles of tumor-bearing mice.

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Castration increased active catabolic TGF-β family myokine proteins in s...
(A–F) Protein expression in GAS muscle. (A) Representative immunoblots of soluble active myostatin (MSTN) C-terminal dimer and eukaryotic elongation factor 2 (EF2) expression in muscle from sets of 4 mice, castrated for the indicated times or sham castrated. Lanes of immunoblots marked “C” contain identical control sample for interblot comparison. (B) Quantification of relative MSTN levels for castrated mice (red) or sham-castrated mice (blue), from 3 determinations for each muscle (see Supplemental Figure 5 for additional immunoblots and supplemental materials for full, uncut gels). ELISA-determined protein levels of soluble active activin AA dimer (C), activin BB dimer (D), activin AB dimer (E), and soluble GDF11 (F), in muscle from 4 mice at each time point, measured 3 times each. (G–L) Protein expression in TRI muscle. (G) Representative immunoblot of MSTN and EF2 expression, as in A. (H) Quantification of MSTN levels, as in B. ELISA-determined protein levels of soluble active activin AA dimer (I), activin BB dimer (J), activin AB dimer (K), and soluble GDF11 (L), from 4 mice at each time point, measured 3 times each. Columns are sham-castrated normalized means at each time; bars are SEM. Individual mouse levels are indicated by open circles. *P < 0.05, **P < 0.01, and ***P < 0.001 versus sham-castrated group determined using 1-way ANOVA and Bonferroni’s correction (B and H) or Dunnett’s test (C–F and I–L).