Myostatin inhibitor

Myostatin inhibitors are a class of drugs that work by blocking the effects 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. 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.[7]

Monoclonal antibodies have been developed that disable myostatin, including apitegromab, domagrozumab, landogrozumab, and stamulumab.[8] Another form of myostatin inhibition is gene therapy.[9]

Another monoclonal antibody, bimagrumab, works as an antagonist of the ACVR2 and ACVR2B receptors, preventing myostatin and activin A from binding.[10] 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.[11]

Clinical trials

Clinical trials of myostatin inhibitors 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.[12] Research is ongoing on the potential use of myostatin inhibitors for motor neuron diseases like spinal muscle atrophy and amyotrophic lateral sclerosis.[13] Due to myostatin's effect as a negative regulator of bone, its inhibition has also been considered for orthopedic diseases such as rheumatoid arthritis.[14]

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.[10]

Bimagrumab showed effectiveness in increasing lean mass and reducing fat mass in obese individuals in a clinical trial.[10]

Performance enhancing drug

It is hypothesized that myostatin inhibitors have an ergogenic effect due to promoting muscle growth.[15] Myostatin inhibitors are banned by the World Anti-Doping Agency.[8]

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.
  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.
  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.
  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: 1–8. doi:10.1038/s44221-023-00136-y. ISSN 2731-6084.
  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. doi:10.1016/j.molstruc.2022.134281.
  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.
  7. 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.
  8. WADA prohibited list section S4.3
  9. 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. doi:10.1073/pnas.0709144105.
  10. 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.
  11. 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.
  12. Wagner, Kathryn R. (October 2020). "The elusive promise of myostatin inhibition for muscular dystrophy". Current Opinion in Neurology. 33 (5): 621. doi:10.1097/WCO.0000000000000853. ISSN 1350-7540.
  13. 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.
  14. 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.
  15. 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.
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