Mechanisms of Testosterone's Anabolic Effects on Muscle and Function: Controversies and New Insights

Testosterone treatment increases muscle mass, maximal voluntary muscle strength, aerobic capacity, and some measures of physical function. Activational and epigenetic mechanisms by which androgens improve muscle mass and physical performance and how to apply these anabolic effects to treat functional limitations associated with aging and disease remain incompletely understood. Testosterone treatment induces hypertrophy of type 1 and 2 muscle fibers and increases muscle progenitor cell numbers by promoting differentiation of mesenchymal progenitor cells into myogenic lineage by an androgen receptor (AR)-mediated pathway. Liganded AR binds to β-catenin, translocates into nucleus where it binds T cell factor-4, and upregulates follistatin that blocks signaling through the TGF-β pathway to promote myogenesis and inhibit adipogenesis. Testosterone increases myoblast proliferation by stimulating polyamine biosynthesis. Stimulation of GH and IGF-1 secretion, intramuscular IGF-1 receptor, and muscle protein synthesis and inhibition of muscle atrophy genes further contribute to testosterone's anabolic effects. Testosterone improves muscle bioenergetics by increasing erythrocytes, oxygen availability, tissue blood flow, and mitochondrial mass and quality. Testosterone increases blood flow by nongenomic mechanisms involving nitric oxide production and calcium and potassium channels in vascular smooth muscle. The conversion of testosterone to 5α-DHT is not required for mediating its anabolic effects. Mechanisms of testosterone's sexually dimorphic epigenetic and tissue-specific activational effects and roles of α-keto reductase and steroid 5α-reductase and 1-carbon and polyamine metabolism in testosterone's actions remain poorly understood. Strategies to translate testosterone-induced muscle mass and strength gains into patient-important improvements in functional performance and health outcomes are needed to enable its clinical applications to treat functional limitations associated with aging and disease.