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F r o m W i k i p e d i a , t h e f r e e e n c y c l o p e d i a
( R e d i r e c t e d f r o m M y o s t a t i n i n h i b i t o r s )
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
[ edit ]
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
[ edit ]
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
[ edit ]
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.[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]
[ edit ]
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
[ edit ]
^ a b 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 .
^ 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 .
^ 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 .
^ a b 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 .
^ 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 .
^ 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 .
^ a b WADA prohibited list section S4.3
^ 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 .
^ a b c 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 .
^ 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 .
^ 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 .
^ 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 .
^ 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 .
^ 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 .
R e t r i e v e d f r o m " https://en.wikipedia.org/w/index.php?title=Myostatin_inhibitor&oldid=1230152605 "
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