Testosterone/androgen receptor antagonizes immobility-induced muscle atrophy through Inhibition of myostatin transcription and inflammation in mice

Abstract

Sarcopenia is caused by excessive muscle protein degradation owing to various factors, including disuse. Although testosterone supplementation is an effective treatment, the underlying molecular mechanisms, particularly the role of the androgen receptor (AR), remain unclear. In this study, we examined the preventive actions of testosterone/AR against muscle atrophy in a murine model of immobilization-induced muscle atrophy. The bilateral hindlimbs of 8-week-old male C57BL/6J mice were immobilized using a wire. Testosterone deficiency and supplementation (50 µg/mL) were conducted by castration and intraperitoneal injection (twice a week for a month), respectively. The results showed a remarkable decline in muscle mass and strength after wire-induced immobilization for 14 days. The expression of muscle atrophic factors (Atrogin1 and MuRF1) and inflammatory factors (F4/80 and interleukin-6 (IL-6)) significantly increased (p < 0.001). Notably, muscular AR expression significantly decreased, whereas myostatin and CCAAT/enhancer-binding protein delta (C/EBPδ), a transcriptional activator of myostatin, were significantly elevated (p < 0.05). After castration, AR expression further decreased, and muscular changes with wire-induced immobilization deteriorated. These exacerbations were completely ameliorated by testosterone supplementation and AR upregulation. Our study provides important therapeutic insights into testosterone/AR in muscular atrophy caused by immobilization and shows that muscular AR in a testosterone-dependent manner regulates C/EBPδ/myostatin and inflammation.