MSTN: A Key Target for Targeted Therapy in Muscle Diseases

Recently, Keros Therapeutics, Inc. announced positive results from the Phase I clinical trial of KER-065 in patients with Duchenne muscular dystrophy, which for the first time confirmed its safety in patients with neuromuscular diseases. KER-065 is a recombinant protein drug targeting the Activin A, MSTN (myostatin) and TGF-β signalling pathways, exerting therapeutic effects by inhibiting these targets. Its indications cover neurological disorders, endocrine and metabolic disorders, genetic diseases and deformities and skin/musculoskeletal disorders, and it may break through the efficacy limitations of traditional single-target drugs in muscular atrophy diseases.

To better understand the potential mechanisms of KER-065, it is necessary to gain an in-depth understanding of the biological background of MSTN and its role in diseases.

1. Background of MSTN

2. Mechanisms and Signalling Pathways of MSTN

3. MSTN-Related Diseases

4. Progress in MSTN Drug Research

5. MSTN-Related Products Recommendation

1. Background of MSTN

Myostatin (MSTN), also known as growth differentiation factor 8 (GDF-8), belongs to the transforming growth factor β (TGF-β) superfamily and is a key negative regulator of skeletal muscle growth. Functional loss or mutations of MSTN can lead to excessive muscle development, manifested as the "double-muscle" phenotype. This was first discovered in Belgian Blue and Piedmontese cattle due to MSTN gene mutations causing muscle hypertrophy ^[1,4,11]. In humans, MSTN functional loss-of-function mutations are associated with congenital muscle hyperplasia ^[7]. In addition to muscle development, MSTN is also involved in the pathogenesis of bone metabolism, fat deposition and the pancreas.

The MSTN gene is highly conserved across species. The precursor protein encoded by it is cleaved by proteases to release the active domain, which binds to and activates the activin type II receptors (ACVR2A/ACVR2B) to transmit signals. In animal breeding ^[2,7], MSTN editing has been used to develop high-lean-meat breeds, such as MSTN -knockout sheep, pigs and chickens, which show significant muscle growth ^[6,12,14].

2. Mechanisms and Signalling Pathways of MSTN

2.1 Core Signalling Pathways

MSTN inhibits muscle growth through the classical TGF-β signalling pathway. Active MSTN binds to ACVR2 receptors, recruits activin receptor-like kinases (ALK4/5/7), phosphorylates Smad2/3 proteins and thereby inhibits myoblast proliferation and differentiation ^[2,7]. In addition, MSTN can regulate muscle metabolism through non-Smad pathways (such as ERK1/2 and p38 MAPK) ^[7,12]. In C2C12 myoblasts, MSTN inhibits the AKT signalling pathway, blocking myotube hypertrophy, while MSTN knockout activates AKT, promoting muscle growth ^[7]. In bovine myoblasts, MSTN mutations lead to reduced phosphorylation levels of Smad2/3 and simultaneously upregulate the BMP signalling pathway, promoting osteogenic differentiation ^[13].

2.2 Tissue-Specific Regulation

Muscle development: MSTN is highly expressed in skeletal muscle and inhibits satellite cell activation and myofibre hypertrophy. MSTN -knockout mice and sheep show a significant increase in myofibre number and diameter ^[6,12].
Bone and fat: GDF11 (an MSTN homolog) promotes osteogenesis by activating the BMP signalling pathway, while MSTN inhibits osteoblast differentiation and promotes osteoclast formation, leading to bone loss ^[7]. Additionally, MSTN inhibits adipocyte differentiation, and its mutations are associated with reduced fat deposition in livestock ^[13].
Pancreatic pathology: Calves with MSTN gene mutations develop lethal pancreatitis due to pancreatic acinar cell necrosis and inflammatory cell infiltration, suggesting that MSTN may be involved in pancreatic homeostasis regulation ^[1].

3. MSTN-Related Diseases

Muscle atrophy and myopathy: Overexpression of MSTN is closely associated with muscle atrophy diseases such as Duchenne muscular dystrophy (DMD) and age-related sarcopenia. Blocking MSTN signalling can improve muscle function in mouse models ^[3,7]. In clinical trials, anti-MSTN antibodies have been shown to increase muscle volume in DMD patients, but with limited functional improvement ^[3].
Metabolic diseases: MSTN inhibits insulin signalling, and its serum levels are positively correlated with obesity and type 2 diabetes. In pig models, MSTN editing reduces fat deposition and improves glucose metabolism ^[13,14].
Bone diseases: MSTN is involved in osteoporosis by inhibiting osteoblast activity and promoting osteoclast formation. MSTN -knockout sheep exhibit increased bone density, while inhibition of GDF11 (which shares receptors with MSTN) leads to reduced bone strength ^[7].

4. Progress in MSTN Drug Research

Recent progress has been made in MSTN drug development. Antibody drugs such as Apitegromab, Emugrobart and Trevogrumab are in different stages of clinical trials. They inhibit MSTN activity through different mechanisms to treat a variety of diseases, such as spinal muscular atrophy, obesity and facioscapulohumeral muscular dystrophy. There are also multiple pipelines in development for small-molecule inhibitors and other types of drugs, some of which have entered the clinical stage, as detailed in the following table:

Drug	Drug Type	Indications	Sponsor	Highest Development Stage
Apitegromab	Monoclonal Antibody	Spinal Muscular Atrophy, Atrophy, Juvenile Spinal Muscular Atrophy, Type II Spinal Muscular Atrophy, Obesity, Muscle Hypertrophy Related to Myostatin	Scholar Rock, Inc.	Filed for Marketing Authorization
Tetasip alfa	Fc Fusion Protein	Spinal Muscular Atrophy, Obesity	Biohaven Pharmaceuticals, Inc. \| Biohaven Ltd.	Phase III Clinical
Emugrobart	Monoclonal Antibody	Spinal Muscular Atrophy, Facioscapulohumeral Muscular Dystrophy, Obesity, Neuromuscular Diseases	Hoffmann-La Roche, Inc. \| Genentech, Inc. \| Roche Holding AG	Phase II/III Clinical
AAV1-FS344	Adeno-Associated Viral Gene Therapy	Duchenne Muscular Dystrophy, Inclusion Body Myositis	Milo Biotechnology LLC \| Nationwide Children's Hospital	Phase II Clinical
Trevogrumab	Monoclonal Antibody	Obesity	Regeneron Pharmaceuticals, Inc.	Phase II Clinical
EL-22	Probiotic	Obesity	MOA Life Plus Co., Ltd.	Phase I Clinical
KER-065	Recombinant Protein	Neuromuscular Diseases, Obesity, Duchenne Muscular Dystrophy	Keros Therapeutics, Inc.	Phase I Clinical

5. MSTN-Related Products Recommendation

Although MSTN inhibitors have shown significant effects in animal models, their clinical translation still faces challenges such as off-target effects, delivery efficiency and safety. CUSABIO provides MSTN-related recombinant proteins, antibodies and ELISA kits to help researchers investigate the mechanisms of MSTN and its clinical translation, and to promote the application of MSTN -targeted therapies in muscle diseases and animal breeding.

● MSTN Recombinant Proteins

Recombinant Human Growth/differentiation factor 8 (MSTN) (Active); CSB-MP015057HU(A4)

● MSTN Antibodies

MSTN Antibody; CSB-PA11869A0Rb

● MSTN ELISA Kits

Human Myostatin, MSTN ELISA Kit

CSB-E11300h

References

[1] Yang, M., Wei, Z., Zhou, X., et al. (2020). A Fatal Case of MSTN Mutation Calf Pancreatitis. Preprints.

[2] Maeta, K., Farea, M., Nishio, H., & Matsuo, M. (2023). A novel splice variant of the human MSTN gene encodes a myostatin-specific myostatin inhibitor. Journal of Cachexia, Sarcopenia and Muscle, 14, 2289-2300.

[3] Campbell, C., et al. (2017). Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial. Muscle & Nerve, 55(4), 458-464.

[4] Grobet, L., Martin, L. J. R., Poncelet, D., et al. (1997). A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nature Genetics, 17(1), 71-74.

[5] McPherron, A. C., Lawler, A. M., & Lee, S. J. (1997). Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member. Nature, 387(6628), 83-90.

[6] Guo, R., Wang, H., Meng, C., et al. (2023). Efficient and Specific Generation of MSTN-Edited Hu Sheep Using C-CRISPR. Genes, 14(6), 1216.

[7] Suh, J., Kim, N. K., Lee, S. H., et al. (2020). GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone. Proceedings of the National Academy of Sciences, 117(9), 4910-4920.

[8] Schuelke, M., Wagner, K. R., Stolz, L. E., et al. (2004). Myostatin mutation associated with gross muscle hypertrophy in a child. New England Journal of Medicine, 350(26), 2682-2688.

[9] Li, R., Zeng, W., Ma, M., et al. (2020). Precise editing of myostatin signal peptide by CRISPR/Cas9 increases the muscle mass of Liang Guang Small Spotted pigs. Transgenic Research, 29(2), 149-163.

[10] Wang, X., Niu, Y., Zhou, J., et al. (2016). Multiplex gene editing via CRISPR/Cas9 exhibits desirable muscle hypertrophy without detectable off-target effects in sheep. Scientific Reports, 6, 32271.

[11] McPherron, A. C., & Lee, S. J. (1997). Double muscling in cattle due to mutations in the myostatin gene. Proceedings of the National Academy of Sciences, 94(23), 12457-12461.

[12] Eom, K.-H., Kwon, D.-H., Kim, Y.-C., et al. (2024). Novel Mammalian Ubiquitous Promoter Isolated from Bovine MSTN Gene Promoter. Preprints.

[13] Zhang, C., Liu, Y., Xu, D., et al. (2011). Polymorphisms of myostatin gene (MSTN) in four goat breeds and their effects on Boer goat growth performance. Molecular Biology Reports, 39(3), 3081-3087.

[14] Li, R., Zeng, W., Ma, M., et al. (2020). CRISPR/Cas9-mediated MSTN disruption accelerates the growth of Chinese Bama pigs. Reproduction in Domestic Animals, 55(6), 1314-1327.

Cite this article

CUSABIO team. MSTN: A Key Target for Targeted Therapy in Muscle Diseases. https://www.cusabio.com/c-21226.html

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MSTN: A Key Target for Targeted Therapy in Muscle Diseases​

1. Background of MSTN

2. Mechanisms and Signalling Pathways of MSTN

2.1 Core Signalling Pathways

2.2 Tissue-Specific Regulation

3. MSTN-Related Diseases

4. Progress in MSTN Drug Research

5. MSTN-Related Products Recommendation

MSTN: A Key Target for Targeted Therapy in Muscle Diseases