The effects of testosterone deprivation and supplementation on proteasomal and autophagy activity in the skeletal muscle of the male mouse: differential effects on high-androgen responder and low-androgen responder muscle groups.

Men with prostate cancer who receive androgen deprivation therapy show profound skeletal muscle loss. We hypothesized that the androgen deficiency activates not only the ubiquitin-proteasome systems but also the autophagy and affects key aspects of the molecular cross talk between protein synthesis and degradation. Here, 2-month-old male mice were castrated and treated with either testosterone (T) propionate or vehicle for 7 days (short term) or 43 days (long term), and with and without hydroxyflutamide. Castrated mice showed rapid and profound atrophy of the levator ani muscle (high androgen responder) at short term and lesser atrophy of the triceps muscle (low androgen responder) at long term. Levator ani and triceps muscles of castrated mice showed increased level of autophagy markers and lysosome enzymatic activity; only the levator ani showed increased proteasomal enzymatic activity. The levator ani muscle of the castrated mice showed increased level and activation of forkhead box protein O3A, the inhibition of mechanistic target of rapamicyn, and the activation of tuberous sclerosis complex protein 2 and 5'-AMP-activated protein kinase. Similar results were obtained in the triceps muscle of castrated mice. T rescued the loss of muscle mass after orchiectomy and inhibited lysosome and proteasome pathways dose dependently and in a seemingly IGF-I-dependent manner. Hydroxyflutamide attenuated the effect of T in the levator ani muscle of castrated mice. In conclusion, androgen deprivation in adult mice induces muscle atrophy associated with proteasomal and lysosomal activity. T optimizes muscle protein balance by modulating the equilibrium between mechanistic target of rapamicyn and 5'-AMP-activated protein kinase pathways.

Testosterone improves the regeneration of old and young mouse skeletal muscle.

Aging is associated with loss of muscle mass and strength, reduced satellite cell number, and lower regenerative potential. Testosterone increases muscle mass, strength, and satellite cell number in humans; however, the effects of testosterone on the regenerative potential of skeletal muscle are unclear. Here, we investigated the effect of testosterone on the skeletal muscle regeneration of young (2-month-old) and aged (24-month-old) male mice. We show that testosterone increases the number of proliferating satellite cells in regenerating "tibialis anterior" muscle of young and aged castrated mice 2 and 4 days postinjury. Testosterone supplementation increases the number and the cross-sectional area of regenerating fibers in both classes of age 4 days postinjury. Testosterone increases satellite cell activation and proliferation and the regeneration of both young and aged mouse muscle. These data suggest prospective application of androgens to improve the regenerating potential of the aged human skeletal muscle.