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Prostate tumor-derived GDF11 accelerates androgen deprivation therapy-induced sarcopenia.

Publication ,  Journal Article
Pan, C; Jaiswal Agrawal, N; Zulia, Y; Singh, S; Sha, K; Mohler, JL; Eng, KH; Chakkalakal, JV; Krolewski, JJ; Nastiuk, KL
Published in: JCI Insight
March 26, 2020

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.

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Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

March 26, 2020

Volume

5

Issue

6

Location

United States

Related Subject Headings

  • Sarcopenia
  • Prostatic Neoplasms
  • Muscle, Skeletal
  • Mice
  • Male
  • Growth Differentiation Factors
  • Bone Morphogenetic Proteins
  • Animals
  • Androgen Antagonists
  • 42 Health sciences
 

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Pan, C., Jaiswal Agrawal, N., Zulia, Y., Singh, S., Sha, K., Mohler, J. L., … Nastiuk, K. L. (2020). Prostate tumor-derived GDF11 accelerates androgen deprivation therapy-induced sarcopenia. JCI Insight, 5(6). https://doi.org/10.1172/jci.insight.127018
Pan, Chunliu, Neha Jaiswal Agrawal, Yanni Zulia, Shalini Singh, Kai Sha, James L. Mohler, Kevin H. Eng, Joe V. Chakkalakal, John J. Krolewski, and Kent L. Nastiuk. “Prostate tumor-derived GDF11 accelerates androgen deprivation therapy-induced sarcopenia.JCI Insight 5, no. 6 (March 26, 2020). https://doi.org/10.1172/jci.insight.127018.
Pan C, Jaiswal Agrawal N, Zulia Y, Singh S, Sha K, Mohler JL, et al. Prostate tumor-derived GDF11 accelerates androgen deprivation therapy-induced sarcopenia. JCI Insight. 2020 Mar 26;5(6).
Pan, Chunliu, et al. “Prostate tumor-derived GDF11 accelerates androgen deprivation therapy-induced sarcopenia.JCI Insight, vol. 5, no. 6, Mar. 2020. Pubmed, doi:10.1172/jci.insight.127018.
Pan C, Jaiswal Agrawal N, Zulia Y, Singh S, Sha K, Mohler JL, Eng KH, Chakkalakal JV, Krolewski JJ, Nastiuk KL. Prostate tumor-derived GDF11 accelerates androgen deprivation therapy-induced sarcopenia. JCI Insight. 2020 Mar 26;5(6).

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

March 26, 2020

Volume

5

Issue

6

Location

United States

Related Subject Headings

  • Sarcopenia
  • Prostatic Neoplasms
  • Muscle, Skeletal
  • Mice
  • Male
  • Growth Differentiation Factors
  • Bone Morphogenetic Proteins
  • Animals
  • Androgen Antagonists
  • 42 Health sciences