Korean J Sports Med.  2022 Jun;40(2):67-85. 10.5763/kjsm.2022.40.2.67.

The Mechanisms of Anabolic Steroids, Selective Androgen Receptor Modulators and Myostatin Inhibitors

• Park J
• Mcllvain V
• Rosenberg J
• Donovan L
• Desai P
• Kim JY

• KMID: 2530310
• DOI: http://doi.org/10.5763/kjsm.2022.40.2.67

Abstract

In the clinical setting, anabolic agents serve to ameliorate muscle- and bone-wasting diseases. However, many of these anabolic agents are also used by bodybuilders to surpass natural limits of body composition as performanceenhancing drugs (PEDs). The first generation of PEDs comprises testosterone-derived anabolic-androgenic steroids (AAS) which have demonstrated significant myotropic effects. However, AAS lack optimal tissue-selectively and thus, are prone to numerous adverse health consequences. Hence, a newer generation of PEDs, selective androgen receptor modulators (SARMs), was developed with the goal of achieving superior tissue-selectivity (i.e., exerting anabolic effects only in muscle and bone tissue, while minimally affecting other body systems). In general, AAS and SARMs enhance muscle growth primarily through androgen receptor (AR) agonism in target tissues. Despite multiple attempts, no single AAS nor SARM to date is completely risk free. As such, a significant portion of research efforts has been dedicated to manipulating anabolic pathways beyond the AR. Another class of PEDs, myostatin inhibitors, have shown to cause drastic muscle anabolism across multiple species by inhibiting myostatin, the primary deterrent to continuous muscle growth. The myostatin inhibitor, YK-11, blocks myostatin by upregulating its antagonist, follistatin. This effect appears to be mediated through the AR, suggesting a novel and promising gene-selective approach to engineering AR ligands that isolate benefits from risks. At any rate, the exact mechanisms by which these PEDs function is not well understood. Further pioneering regarding these topics is encouraged as it appears that the innovation of a truly tissue-selective anabolic agent is within reach.

Keyword

Steroids; Performance-enhancing substances; Resistance training; Androgen receptor agonists; Myostatin

Figure

• 

  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.

• 

  Fig. 2 Potential mechanism of selective androgen receptor modulator (SARM) tissue-selectivity based on the coactivator hypothesis. As shown in box C and D, testosterone exerts approximately equal androgen receptor (AR) agonism in both androgenic tissue (i.e., prostate) and anabolic tissue (i.e., skeletal muscle tissue). This likely results from a similar coregulator recruitment and/or ligand-AR complex conformation in both types of tissues. On the other hand, SARMs appear to have partial agonist/weak antagonist activity on the AR in androgenic tissues as a result of recruiting more corepressors than coactivators compared to testosterone/dihydrotestosterone (DHT) (compare boxes A and C). In anabolic tissues, SARMs are shown to preferentially recruit coactivators over corepressors and exert full AR agonist activity, often with a greater magnitude than anabolic-androgenic steroid in the same tissue (compare boxes B and D). HSP: heat shock proteins, 5AR: 5-α-reductase.

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