A potent liver-mediated mechanism for loss of muscle mass during androgen deprivation therapy

Author:

Lam Teresa123,McLean Mark12,Hayden Amy45,Poljak Anne6,Cheema Birinder7,Gurney Howard5,Stone Glenn8,Bahl Neha1,Reddy Navneeta29,Shahidipour Haleh121011,Birzniece Vita1291011

Affiliation:

1. 1School of Medicine, Western Sydney University, Penrith, New South Wales, Australia

2. 2Department of Diabetes and Endocrinology, Blacktown Hospital, Blacktown, New South Wales, Australia

3. 3Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, New South Wales, Australia

4. 4Department of Radiation Oncology, Blacktown Hospital, Blacktown, New South Wales, Australia

5. 5Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia

6. 6Bioanalytical Mass Spectrometry Facility and School of Medical Sciences, UNSW Sydney, Sydney, New South Wales, Australia

7. 7School of Science and Health, Western Sydney University, Penrith, New South Wales, Australia

8. 8School of Computing, Engineering and Mathematics, Western Sydney University, Penrith, New South Wales, Australia

9. 9Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

10. 10School of Medicine, UNSW Sydney, Sydney, New South Wales, Australia

11. 11Translational Health Research Institute, Penrith, New South Wales, Australia

Abstract

Context Androgen deprivation therapy (ADT) in prostate cancer results in muscular atrophy, due to loss of the anabolic actions of testosterone. Recently, we discovered that testosterone acts on the hepatic urea cycle to reduce amino acid nitrogen elimination. We now hypothesize that ADT enhances protein oxidative losses by increasing hepatic urea production, resulting in muscle catabolism. We also investigated whether progressive resistance training (PRT) can offset ADT-induced changes in protein metabolism. Objective To investigate the effect of ADT on whole-body protein metabolism and hepatic urea production with and without a home-based PRT program. Design A randomized controlled trial. Patients and intervention Twenty-four prostate cancer patients were studied before and after 6 weeks of ADT. Patients were randomized into either usual care (UC) (n = 11) or PRT (n = 13) starting immediately after ADT. Main outcome measures The rate of hepatic urea production was measured by the urea turnover technique using 15N2-urea. Whole-body leucine turnover was measured, and leucine rate of appearance (LRa), an index of protein breakdown and leucine oxidation (Lox), a measure of irreversible protein loss, was calculated. Results ADT resulted in a significant mean increase in hepatic urea production (from 427.6 ± 18.8 to 486.5 ± 21.3; P < 0.01) regardless of the exercise intervention. Net protein loss, as measured by Lox/Lra, increased by 12.6 ± 4.9% (P < 0.05). PRT preserved lean body mass without affecting hepatic urea production. Conclusion As early as 6 weeks after initiation of ADT, the suppression of testosterone increases protein loss through elevated hepatic urea production. Short-term PRT was unable to offset changes in protein metabolism during a state of profound testosterone deficiency.

Publisher

Bioscientifica

Subject

Endocrinology,Endocrinology, Diabetes and Metabolism,Internal Medicine

Reference96 articles.

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