Hier heb ik een citaat van een bekend onderzoek die ik recent gevolgd heb.
The selective androgen receptor modulators (SARMs) are a group of chemically synthesized small molecules that function as agonists/antagonists of AR. Similar to testosterone, the interaction of SARM and AR intrigues the translocation of the complex to nuclear. Unlike testosterone-AR complex, different SARM-AR complexes selectively recruit different regulatory proteins and transcriptional factors to modulate gene expression. Due to this selectivity along with the tissue-dependent variation in AR’s expressional pattern and regulatory protein profile, SARM-ARs display tissue-specific signaling. Therefore, SARMs therapy can facilitate tissue-specific benefits without off-target side effects.
59 SARMs studies only started in the late 20th century. With a significant anabolic activity in muscle and bone, but minimal to moderate androgenic side effects, several SARMs in preclinic studies, such as MK-0773, GTx-024, and GSK2881078, shows a great potential to treat muscle wasting associated conditions, including sarcopenia.
MK-0773 has completed a phase II trial in women with mobility disabilities (NCT00529659: completed in 2009). MK-0773 treatment for 6 months significantly increased lean body mass without evidence of androgenization. However, there is no significant improvement in muscular strength or physical performance.
60 GTx-024 was considered as a future star because it showed a dose-dependent improvement in total lean body mass and physical function and was well tolerated in its phase II trial in healthy elderly men and postmenopausal women.
61 However, it failed in the phase III trial (NCT01355497 and NCT01355484, completed in 2014) to prevent and treat muscle wasting in patients with non-small cell lung cancer. Similar to MK-0773, GTx-024 treatment for 3 months significantly improved lean body mass but not physical function measured by the stair climb test.
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64 GSK2881078 treatment showed a dose-dependent gain in lean body mass in a phase I trial in healthy old men and women.
65 A phase II trial (NCT03359473, completed in 2019) was conducted to evaluate GSK2881078’s safety and effect on physical strength and function in both postmenopausal female and older male subjects with COPD and muscle weakness. Interestingly, the trial is the first one to evaluate a treatment that combined SARMs with exercise by adding a 13-week exercise program after a 30-day treatment of GSK2881078. The final evaluation is still underway and has not been published yet.
S42, another SARM newly developed in 2009, has shown the potential for muscle growth in an
in vitro model (C2C12 muscle cell line). It positively impacts on muscle hypertrophy by activating Akt/mTORC1/p70S6K signaling to promote protein synthesis, and negatively impacts on muscle atrophy by suppressing the expression of MuRF1 and atrogin1 to inhibit protein degradation.
