YK-11 and Obstacles to Myostatin Blockade
YK-11 is a steroidal gene-selective partial agonist of the AR, or in other words, a SARM. Inhibiting myostatin by targeting the AR is possible because both myostatin and follistatin are subject to androgen signaling. In C2C12 myoblast cells, additional key anabolic targets of the AR such as MyoG, Mfy5, and MyoD are upregulated with the administration of YK-11.
Myogenic effects of YK-11 also involve NF-κB signaling as it has been suggested to attenuate muscle wasting during sepsis. Unlike full AR agonists, YK-11 prevents N/C interaction, and it has been suggested that YK-11 may also interfere with the ability of other AR ligands (i.e., DHT) to induce conformational changes to the AR necessary for full activation. This characteristic poses a potential limitation when combining YK-11 with a wide range of PEDs because AAS and other SARMs highly depend on full AR agonism to exert their myotropic effects.
Furthermore, there are numerous other barriers to myostatin inhibitors. Gum bleeding, telangiectasia, and erythema following soluble ActRIIB administration has hindered its clinical progression. Myostatin inhibitors that function via follistatin upregulation also have their own drawbacks. Follistatin inhibits pituitary FSH release, and thus, artificially upregulating follistatin harms fertility. With respect to safety and efficacy, YK-11 has yet to be tested in human clinical trials. However, there are certainly a significant number of athletes who have used the PED, demonstrated by the development of drug tests for YK-11 in athletic competitions.
Myostatin inhibition, at least via follistatin upregulation, may also increase the risk of injury in athletes. Tendons of myostatin knockout rats have 20% less peak strain compared to wild-type controls. Similar treatments in mice caused comparable effects, resulting in tendons that were small, brittle, and hypocellular. Follistatin knockout mice exhibit craniofacial and rib defects. As such, TGF-β superfamily members appear to regulate the balance between stem cells and tissue homeostasis beyond skeletal muscle tissue. With respect to resistance exercise adaptations, myostatin may serve to ensure tendon integrity to match the increasing tensile load generated by growing contractile protein tissue.
Consequently, one should practice extra caution when utilizing myostatin inhibitors due to their potential to increase injury risk. Further research may reveal novel insight on the dichotomous tissue-specific nature of TGF-β expression in response to androgen signaling. For instance, androgens like DHT tend to promote facial hair growth but simultaneously induce the miniaturization of scalp hair follicles in those prone to androgenic alopecia.
Perhaps all AR ligands, AAS included, maintain gene-selective effects depending on the tissue type and corresponding unique cellular milieus composing distinct coregulator profiles and epigenomes. This may further explain differing physiological effects of various androgens and suggests the possibility of engineering new AR ligands through a gene- and/or epigene-selective approach. Nonetheless, myostatin inhibition as a whole remains another relatively untapped field for novel anabolic agents.
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