Monitoring gene expression in muscle tissue of macaca fascicularis under the influence of testosterone and SARM.

Abstract

The focus of this study was to evaluate data on the gene expression profiles induced by testosterone and a selective androgen receptor modulator (SARM, TAP Pharmaceutical Products Inc., Lake Forest, IL, USA) in androgen sensitive muscle tissue to obtain a better understanding on the molecular mechanisms of action and to identify biomarkers for SARM function in primate organs. A total of 24 male cyomolgus monkeys were divided into four groups: testosterone group, SARM1 group, SARM10 group, and control group, each consisting of six animals. The testosterone group was treated i.m. with 3.0 mg/kg Testostoviron®-depot-250 (Schering, Berlin, Germany) every 2 weeks, the SARM1 and SARM10 groups with 1 mg/kg or 10 mg/kg SARM LGD2941 daily, and the control group was not treated. Muscle biopsies from musculus quadriceps and musculus triceps were collected at three time points: baseline time point before SARM application (control), on day 16, and on day 90 of treatment. A total of 30 candidate genes were selected according to their functionality by screening the actual literature and were composed to the following functional groups: cell cycle, endocrine factors, energy metabolism, muscle fiber proteins, muscle specific transcription factors, protein metabolism, and satellite cell biology. Biomarkers were identified as genes regulated from baseline in any of the three treatment groups at day 16 or day 90 using analysis of variance with baseline defined as the contrast group. Out of 23 tested candidate genes, 3 were significantly regulated in m. quadriceps after 90 days treatment; in m. triceps no significant differences were identified. Cathepsin L, calpain 3, and insulin like growth factor binding protein 3 could be identified as first biomarkers, and first physiological differences between control and treatment samples were determined. Both testosterone and SARM LGD2941 appear to have similar effects after 90 days treatment, and thus a longer-term therapy with these substances can be recommended.

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