Myostatin inhibitor

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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.

Contents

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]

Related Research Articles

<span class="mw-page-title-main">Atrophy</span> Partial or complete wasting away of a part of the body

Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations, poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, excessive amount of apoptosis of cells, and disuse or lack of exercise or disease intrinsic to the tissue itself. In medical practice, hormonal and nerve inputs that maintain an organ or body part are said to have trophic effects. A diminished muscular trophic condition is designated as atrophy. Atrophy is reduction in size of cell, organ or tissue, after attaining its normal mature growth. In contrast, hypoplasia is the reduction in the cellular numbers of an organ, or tissue that has not attained normal maturity.

<span class="mw-page-title-main">Myostatin</span> Mammalian and avian protein

Myostatin is a protein that in humans is encoded by the MSTN gene. Myostatin is a myokine that is produced and released by myocytes and acts on muscle cells to inhibit muscle growth. Myostatin is a secreted growth differentiation factor that is a member of the TGF beta protein family.

<span class="mw-page-title-main">Spinal and bulbar muscular atrophy</span> Medical condition

Spinal and bulbar muscular atrophy (SBMA), popularly known as Kennedy's disease, is a rare, adult-onset, X-linked recessive lower motor neuron disease caused by trinucleotide CAG repeat expansions in exon 1 of the androgen receptor (AR) gene, which results in both loss of AR function and toxic gain of function.

<span class="mw-page-title-main">Hypothalamic–pituitary–gonadal axis</span> Concept of regarding the hypothalamus, pituitary gland and gonadal glands as a single entity

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

<span class="mw-page-title-main">Sarcopenia</span> Muscle loss due to ageing or immobility

Sarcopenia is a type of muscle loss that occurs with aging and/or immobility. It is characterized by the degenerative loss of skeletal muscle mass, quality, and strength. The rate of muscle loss is dependent on exercise level, co-morbidities, nutrition and other factors. The muscle loss is related to changes in muscle synthesis signalling pathways. It is distinct from cachexia, in which muscle is degraded through cytokine-mediated degradation, although the two conditions may co-exist. Sarcopenia is considered a component of frailty syndrome. Sarcopenia can lead to reduced quality of life, falls, fracture, and disability.

<span class="mw-page-title-main">Muscle atrophy</span> Loss of skeletal muscle mass

Muscle atrophy is the loss of skeletal muscle mass. It can be caused by immobility, aging, malnutrition, medications, or a wide range of injuries or diseases that impact the musculoskeletal or nervous system. Muscle atrophy leads to muscle weakness and causes disability.

<span class="mw-page-title-main">Mothers against decapentaplegic homolog 3</span> Protein-coding gene in humans

Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene.

<span class="mw-page-title-main">Follistatin</span> Mammalian protein found in Homo sapiens

Follistatin, also known as activin-bindings protein, is a protein that in humans is encoded by the FST gene. Follistatin is an autocrine glycoprotein that is expressed in nearly all tissues of higher animals.

The activin type 2 receptors belong to a larger TGF-beta receptor family and modulate signals for transforming growth factor beta ligands. These receptors are involved in a host of physiological processes including, growth, cell differentiation, homeostasis, osteogenesis, apoptosis and many other functions. There are two activin type two receptors: ACVR2A and ACVR2B.

<span class="mw-page-title-main">Muscle hypertrophy</span> Enlargement or overgrowth of a muscle organ

Muscle hypertrophy or muscle building involves a hypertrophy or increase in size of skeletal muscle through a growth in size of its component cells. Two factors contribute to hypertrophy: sarcoplasmic hypertrophy, which focuses more on increased muscle glycogen storage; and myofibrillar hypertrophy, which focuses more on increased myofibril size. It is the primary focus of bodybuilding-related activities.

<span class="mw-page-title-main">GDF11</span> Protein-coding gene in humans

Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP-11), is a protein that in humans is encoded by the growth differentiation factor 11 gene. GDF11 is a member of the Transforming growth factor beta family.

<span class="mw-page-title-main">Selective androgen receptor modulator</span> Class of pharmaceutical drugs

Selective androgen receptor modulators (SARMs) are a class of drugs that selectively activate the androgen receptor in specific tissues, promoting muscle and bone growth while having less effect on male reproductive tissues like the prostate gland.

<span class="mw-page-title-main">Sarcopenic obesity</span> Medical condition: obesity and loss of muscle

Sarcopenic obesity is a combination of two disease states, sarcopenia and obesity. Sarcopenia is the muscle mass/strength/physical function loss associated with increased age, and obesity is based off a weight to height ratio or body mass index (BMI) that is characterized by high body fat or being overweight.

<span class="mw-page-title-main">Enobosarm</span> Investigational selective androgen receptor modulator

Enobosarm, also formerly known as ostarine and by the developmental code names GTx-024, MK-2866, and S-22, is a selective androgen receptor modulator (SARM) which is under development for the treatment of androgen receptor-positive breast cancer in women and for improvement of body composition in people taking GLP-1 receptor agonists like semaglutide. It was also under development for a variety of other indications, including treatment of cachexia, Duchenne muscular dystrophy, muscle atrophy or sarcopenia, and stress urinary incontinence, but development for all other uses has been discontinued. Enobosarm was evaluated for the treatment of muscle wasting related to cancer in late-stage clinical trials, and the drug improved lean body mass in these trials, but it was not effective in improving muscle strength. As a result, enobosarm was not approved and development for this use was terminated. Enobosarm is taken by mouth.

Double-muscled cattle are breeds of cattle that carry one of seven known mutations that limits and reduces the activity of the myostatin protein. Normally, myostatin limits the number of muscle fibers present at birth, and interfering with activity of this protein causes animals to be born with higher numbers of muscle fibers, consequently augmenting muscle growth. Additionally, these mutations reduce the superficial and internal fat deposits, causing the meat to be less marbled and lower in fat content. Animals homozygous for myostatin mutation also have improved meat tenderness in some cuts of meat. The enlarged muscles of dam and calf at birth leads to increased difficulty of calving, and in some breeds frequently necessitates birth by cesarean section.

<span class="mw-page-title-main">Activin and inhibin</span> Regulators of feedback on FSH-production

Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual cycle. Many other functions have been found to be exerted by activin, including roles in cell proliferation, differentiation, apoptosis, metabolism, homeostasis, immune response, wound repair, and endocrine function. Conversely, inhibin downregulates FSH synthesis and inhibits FSH secretion. The existence of inhibin was hypothesized as early as 1916; however, it was not demonstrated to exist until Neena Schwartz and Cornelia Channing's work in the mid-1970s, after which both proteins were molecularly characterized ten years later.

A myokine is one of several hundred cytokines or other small proteins and proteoglycan peptides that are produced and released by skeletal muscle cells in response to muscular contractions. They have autocrine, paracrine and/or endocrine effects; their systemic effects occur at picomolar concentrations.

Bimagrumab (BYM338) is a human monoclonal antibody developed by Novartis to treat pathological muscle loss and weakness. It binds to and inhibits activin receptor type-2B.

<span class="mw-page-title-main">Decoy receptors</span>

A decoy receptor is a receptor that is able to recognize and bind specific growth factors or cytokines efficiently, but is not structurally able to signal or activate the intended receptor complex. It acts as an inhibitor, binding a ligand and keeping it from binding to its regular receptor. Decoy receptors participate in a common methods of signal inhibition and are also abundant in malignant tissues, making up a significant topic in cancer research.

<span class="mw-page-title-main">MK-0773</span> Abandoned drug

MK-0773, also known as PF-05314882, is a steroidal, orally active selective androgen receptor modulator (SARM) that was under development by Merck and GTx for the treatment of sarcopenia in women and men. Clinical trials for sarcopenia began in late 2007 but the collaboration between Merck and GTx ended in early 2010 and GTx terminated development of MK-0773 shortly thereafter. MK-0773 was developed as a more advanced version of the related compound TFM-4AS-1.

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. 1 2 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. 1 2 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. 1 2 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. 1 2 3 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.
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