Background: Androgen deprivation therapy (ADT) leads to decreases in muscle mass and function. As yet, no human studies have investigated the cellular or genetic effects on skeletal muscle. Understanding testosterone-regulated signalling pathways has implications to aid discovery of novel therapeutics for treatment of sarcopenia. We aimed to determine changes in gene expression in skeletal muscle in men undergoing ADT.
Methods: 9 men with localised prostate cancer underwent percutaneous skeletal muscle biopsies prior to commencement of ADT and 4 weeks post-ADT initiation. Next-generation RNA sequencing was performed (Australian Genome Research Facility Ltd) on RNA extracted from the samples. Genes differentially expressed following ADT underwent gene ontology mining using Ingenuity Pathway Analysis software. Differential expression of genes of interest was confirmed with quantitative PCR (qPCR) in gastrocnemius muscle of orchidectomised mice and sham controls, (n=11/group).
Results: Total testosterone decreased from 16.5±4.3 nmol/L at baseline to 0.4±0.15 nmol/L at one month post-ADT (p<0.001) in the 9 men. No histological changes in fibre type, size or mitochondrial activity were observed. RNA sequencing identified 19 differentially expressed genes post-ADT (all pABCG1, ACTC1, ANKRD1, DMPK, THY1, DCLK1, CST3 were upregulated and SLC38A3 was downregulated post-ADT. qPCR in mouse gastrocnemius muscle confirmed that only one gene, Actc1 was concordantly upregulated (p<0.01) in orchidectomised mice compared with sham.
Conclusions: Given that ACTC1 upregulation is associated with improved muscle function in certain myopathies(1), we speculate that upregulation of ACTC1 may represent a compensatory response to ADT-induced muscle loss. Further studies will be required to evaluate the role and function of ACTC1.