Myostatin inhibitor

Myostatin inhibitors are a class of drugs that work by blocking the effect of myostatin, which inhibits muscle growth. In animal models and limited human studies, myostatin inhibitors have increased muscle size. They are being developed to treat obesity, sarcopenia, muscular dystrophy, and other illnesses.

Background

Myostatin, a member of the transforming growth factor superfamily, is a negative regulator of bone and muscle growth. It may also play a role in obesity, insulin resistance, cardiovascular disease, and chronic kidney disease.[1][2]

Mechanisms

Follistatin is an endogenous protein that negatively regulates myostatin.[3]

Reduction of myostatin expression is one of the mechanisms for the effects of androgens in promoting muscle growth. Androgens both regulate myostatin expression directly and upregulate follistatin expression.[3] YK-11, a selective androgen receptor modulator, is also a myostatin inhibitor.[4][5]

Resistance training reduces myostatin activity and increases follistatin activity.[6] Pharmacological myostatin inhibitors can therefore be considered exercise mimetics.[7] Creatine, a popular workout supplement, has shown some myostatin inhibitory effects in preclinical studies.[6]

Many drugs in development as myostatin inhibitors also reduce the activity of related proteins such as GDF11, activins, and bone morphogenetic proteins. While this off target activity can increase their effectiveness in promoting anabolism, it also increases the risk of adverse effects.[8]

Monoclonal antibodies have been developed that disable myostatin, including apitegromab, domagrozumab, landogrozumab, and stamulumab.[9] Another form of myostatin inhibition is gene therapy.[10]

Another monoclonal antibody, bimagrumab, works as an antagonist of the ACVR2 and ACVR2B receptors, preventing myostatin and activin A from binding.[11] Because activin A reduces erythropoiesis, targeting the ACVR receptors and inhibiting activin A activity can increase the risk of venous thromboembolism in patients who are not anemic.[12]

Clinical trials

Clinical trials for muscular dystrophy have not proven successful in generating functional improvements compared to placebo. Gains of muscle mass were small to non-existent in this population.[13] Research is ongoing on the potential use of myostatin inhibitors for motor neuron diseases like spinal muscle atrophy and amyotrophic lateral sclerosis.[14] Due to myostatin's effect as a negative regulator of bone, its inhibition has also been considered for orthopedic diseases such as rheumatoid arthritis.[15]

Myostatin inhibitors were generally able to increase lean body mass and reduce body fat in people with sarcopenia, but the extent to which this translated into functional improvements varied.[11]

Bimagrumab showed effectiveness in increasing lean mass and reducing fat mass in obese individuals in a clinical trial.[11]

Performance enhancing drug

It is hypothesized that myostatin inhibitors have an ergogenic effect due to promoting muscle growth.[16] Myostatin inhibitors are banned by the World Anti-Doping Agency.[9]

References

1. Mitra, Akash; Qaisar, Rizwan; Bose, Bipasha; Sudheer, Shenoy P (March 2023). "The elusive role of myostatin signaling for muscle regeneration and maintenance of muscle and bone homeostasis". Osteoporosis and Sarcopenia. 9 (1): 1–7. doi:10.1016/j.afos.2023.03.008. PMC 10111947. PMID 37082359.
2. Esposito, Pasquale; Picciotto, Daniela; Battaglia, Yuri; Costigliolo, Francesca; Viazzi, Francesca; Verzola, Daniela (2022). "Myostatin: Basic biology to clinical application". Advances in Clinical Chemistry. 106: 181–234. doi:10.1016/bs.acc.2021.09.006. ISBN 9780323988377. PMID 35152972. S2CID 246774167.
3. Rodriguez, J.; Vernus, B.; Chelh, I.; Cassar-Malek, I.; Gabillard, J. C.; Hadj Sassi, A.; Seiliez, I.; Picard, B.; Bonnieu, A. (1 November 2014). "Myostatin and the skeletal muscle atrophy and hypertrophy signaling pathways". Cellular and Molecular Life Sciences. 71 (22): 4361–4371. doi:10.1007/s00018-014-1689-x. ISSN 1420-9071. PMC 11113773. PMID 25080109. S2CID 253598781.
4. Shimko, Katja M.; O’Brien, Jake W.; Tscharke, Benjamin J.; Brooker, Lance; Goebel, Catrin; Shiels, Ryan; Speers, Naomi; Mueller, Jochen F.; Thomas, Kevin V. (9 October 2023). "Emergence and occurrence of performance-enhancing substance use in Australia determined by wastewater analysis". Nature Water. 1 (10): 879–886. doi:10.1038/s44221-023-00136-y. ISSN 2731-6084. S2CID 263824362.
5. Turza, Alexandru; Borodi, Gheorghe; Miclaus, Maria; Muresan-Pop, Marieta (February 2023). "Exploring the polymorphism of selective androgen receptor modulator YK11". Journal of Molecular Structure. 1273: 134281. Bibcode:2023JMoSt127334281T. doi:10.1016/j.molstruc.2022.134281. S2CID 252741616.
6. de Carvalho, Marianna Rabelo; Duarte, Ellen Fernandes; Mendonça, Maria Lua Marques; de Morais, Camila Souza; Ota, Gabriel Elias; Gaspar-Junior, Jair José; de Oliveira Filiú, Wander Fernando; Damatto, Felipe Cesar; Okoshi, Marina Politi; Okoshi, Katashi; Oliveira, Rodrigo Juliano; Martinez, Paula Felippe; de Oliveira-Junior, Silvio Assis (8 May 2023). "Effects of Creatine Supplementation on the Myostatin Pathway and Myosin Heavy Chain Isoforms in Different Skeletal Muscles of Resistance-Trained Rats". Nutrients. 15 (9): 2224. doi:10.3390/nu15092224. ISSN 2072-6643. PMC 10181225. PMID 37432386.
7. Allen, David L.; Hittel, Dustin S.; McPherron, Alexandra C. (October 2011). "Expression and Function of Myostatin in Obesity, Diabetes, and Exercise Adaptation". Medicine and Science in Sports and Exercise. 43 (10): 1828–1835. doi:10.1249/MSS.0b013e3182178bb4. ISSN 0195-9131. PMC 3192366. PMID 21364474.
8. Suh, Joonho; Lee, Yun-Sil (August 2020). "Myostatin Inhibitors: Panacea or Predicament for Musculoskeletal Disorders?". Journal of Bone Metabolism. 27 (3): 151–165. doi:10.11005/jbm.2020.27.3.151. ISSN 2287-6375. PMC 7571243. PMID 32911580.
9. WADA prohibited list section S4.3
10. Haidet, Amanda M.; Rizo, Liza; Handy, Chalonda; Umapathi, Priya; Eagle, Amy; Shilling, Chris; Boue, Daniel; Martin, Paul T.; Sahenk, Zarife; Mendell, Jerry R.; Kaspar, Brian K. (18 March 2008). "Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors". Proceedings of the National Academy of Sciences. 105 (11): 4318–4322. Bibcode:2008PNAS..105.4318H. doi:10.1073/pnas.0709144105. PMC 2393740. PMID 18334646.
11. Lee, Se-Jin; Bhasin, Shalender; Klickstein, Lloyd; Krishnan, Venkatesh; Rooks, Daniel (16 June 2023). "Challenges and Future Prospects of Targeting Myostatin/Activin A Signaling to Treat Diseases of Muscle Loss and Metabolic Dysfunction". The Journals of Gerontology: Series A. 78 (Supplement_1): 32–37. doi:10.1093/gerona/glad033. PMC 10272974. PMID 36738276.
12. Lodberg, Andreas; van der Eerden, Bram C. J.; Boers-Sijmons, Bianca; Thomsen, Jesper Skovhus; Brüel, Annemarie; van Leeuwen, Johannes P. T. M.; Eijken, Marco (May 2019). "A follistatin-based molecule increases muscle and bone mass without affecting the red blood cell count in mice". The FASEB Journal. 33 (5): 6001–6010. doi:10.1096/fj.201801969RR. PMID 30759349. S2CID 73422507.
13. Wagner, Kathryn R. (October 2020). "The elusive promise of myostatin inhibition for muscular dystrophy". Current Opinion in Neurology. 33 (5): 621–628. doi:10.1097/WCO.0000000000000853. ISSN 1350-7540. PMID 32773450. S2CID 221101583.
14. Abati, Elena; Manini, Arianna; Comi, Giacomo Pietro; Corti, Stefania (21 June 2022). "Inhibition of myostatin and related signaling pathways for the treatment of muscle atrophy in motor neuron diseases". Cellular and Molecular Life Sciences. 79 (7): 374. doi:10.1007/s00018-022-04408-w. ISSN 1420-9071. PMC 9213329. PMID 35727341.
15. Cui, Yinxing; Yi, Qian; Sun, Weichao; Huang, Dixi; Zhang, Hui; Duan, Li; Shang, Hongxi; Wang, Daping; Xiong, Jianyi (January 2023). "Molecular basis and therapeutic potential of myostatin on bone formation and metabolism in orthopedic disease". BioFactors. 49 (1): 21–31. doi:10.1002/biof.1675. ISSN 0951-6433. PMID 32997846. S2CID 222157656.
16. Fedoruk, M. N.; Rupert, J. L. (April 2008). "Myostatin inhibition: a potential performance enhancement strategy?". Scandinavian Journal of Medicine & Science in Sports. 18 (2): 123–131. doi:10.1111/j.1600-0838.2007.00759.x. ISSN 0905-7188. PMID 18248537. S2CID 25355086.