Fig. 1. Anabolic-androgenic steroid (AAS) signaling in myogenesis. AAS exerts many of their effects through androgen receptor (AR) agonism and the transcription/translation of AR target genes. AAS can inhibit muscle protein breakdown (MPB) by antagonizing the glucocorticoid receptor (GR) and also via AR agonism which leads to FOXO and glycogen synthase kinase 3-β (GSK3-β) inhibition, as well as calcium mobilization which inhibits myostatin through calcium-dependent pathways. Inhibition of GSK3-β promotes glycogen synthesis. Combined with nitric oxide release and vasodilation, glycogen synthesis enhances skeletal muscle perfusion during exercise, contributing to efficient training. Aggression and augmented motor unit recruit are some effects of androgens on the nervous system and these effects further promote efficient training by facilitating heavy lifting and training intensity. In bone marrow, androgens promote erythropoiesis, leading to an increased hematocrit that enhances aerobic endurance. Upregulation of myocyte enhancer factor 2 (MEF2)-related genes and ornithine decarboxylase 1 (Odc1), as well as insulin-like growth factor 1 (IGF-1) and mammalian target of rapamycin (mTOR), enhance satellite cell recruitment in numerous ways (i.e., delayed proliferation period, enhanced fusion index, and accompanying the necessary muscle protein synthesis [MPS]). Some AAS serve as substrates for aromatase and/or 5-α-reductase (5AR) and possess additional pathways that may augment or diminish their overall anabolic effects. In general, aromatizable AAS can convert into estrogens and agonize the estrogen receptor (ER) which further supports IGF-1 and arachidonic acid (AA) upregulation. IGF-1 is a major activator of mTOR, while AA optimizes acute inflammation signaling and increases training efficiency. AAS that are 5AR-reductable have differing effects depending on the generated 5AR-modified AAS. For instance, testosterone is reduced into a more potent androgen, while nandrolone is reduced into a weaker androgen. Thus, the biotransformation by 5AR/aromatase and the bioactivity of the resulting steroid hormone are specific to the AAS and tissue. Some relationships and signaling pathways are not shown for the purpose of simplicity.
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