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Function

Structure and synthesis

Primary and secondary structures

Myostatin is a 42,7 kDa protein consisting of only 108 residues in its mature form. It contains 7 cysteine residues in its C-terminal domain, all of which are involved in disulfide bridges. The secondary structure of Myostatin is composed of two strands, both made of short antiparallel structures. This structure is made of 3 alpha helices :

- Helix alpha-1 : containing only between 4 and 7 residues

- Helix alpha-2 : containing between 24 and 28 residues

- Helix alpha-3 : containing between 58 and 68 residues

The folding of these structures gives Myostatin a slightly bent, hand-like shape, with 2 fingers formed by the strands described above. The palm of the hand is formed by the Helix alpha-3. The N- and C-terminal ends are situated very close to the palm and the 10 residues on the N-term side form the thumb of the hand.

The structural analysis of myostatin^[3] was achieved thanks to the proton nuclear magnetic resonance method.

Main partners related to the structure

When in its homodimeric mature form, Myostatin is able to link with several other partners. First of all, Myostatin partners with two types of receptors : ALK 4 and ALK 5 (Activin receptor-Like Kinase). Moreover, the active form of the protein is able to link with the ActRIIB protein (Activin type II Receptor). The action of Myostatin actually requires the binding of it to these two types of membrane receptors.

Myostatin can also bind to diverse partners, ensuing different results :

- The Myostatin-associated protein hSGT (human Small Glutamine-rich Tetratricopeptide repeat-containing protein) binds to myostatin on its N-terminal end. Recent studies suggest that hSGT is involved in the regulation of the secretion and activation of myostatin.

- The association of Myostatin to the Titine-Cap protein enables to regulate the secretion of pre-myostatin in pre-myogenic cells.

- Follistatin is able to for complexes with Myostatin, enabling the inhibition of the Myostatin’s action on muscular development.

- Decorin binds to Myostatin in the muscles and is responsible for the modulation of the activity of Myostatin in myogenic cells.

- The binding of Myostatin with proteins WFIKKN1 and WFIKKN2 (large extracellular multidomain proteins) is responsible for the inhibition of Myostatin.

Synthesis and assembly

In mammals, mature Myostatin consists in a small homodimer. The immature form, called pre-Myostatin, is made of a complex of two non-covalently bound N-terminal propeptides along with C-terminal ends linked by a disulfide bridge. Both C-terminal ends of the pro-peptides are similar regarding their composition in amino-acids, allowing for the formation of a stabilized dimer thanks to a specific inter-chain disulfide bridge. Following its maturation, Myostatin is eventually produced in a shortened form compared to its initial synthesized sequence.

Maturation process

The pre-Myostatin dimer is first cleaved by a protease of the Furin family to the 266 and 267 amino-acids level, namely right before the beginning of the C-terminal end of each pro-peptide. This leads to the formation of a latent pre-Myostatin complex, made of both disulfide-linked C-terminal ends with both N-terminal propeptide next to it. Then comes a protease specific of growth factors, which will provoke the degradation of the N-terminal ends, resulting in the formation of the mature Myostatin homodimer.

Disease/Research

Myostatin ^[4] is a protein that has a control over muscle development: it is a negative regulator of squeletics muscles. It has a very important role during the development of the animals but also during its whole life. It is a very important protein that is very conserved from zebra fish to humans ^[5] and so it has to be very well regulated. Indeed, there are many ways that regulates the action of this protein and at many scales.

It is a grown factor^[5] that is implicated into muscle development in mammals. Myostatin can transmit a message to the nucleus that will promote a gene that lead to the production of ubiquitin. Ubiquitin is a signal of degradation so muscle cells will be destroyed. Indeed, it reduce the mass of the muscle but it also reduces the quantity of Myosin ^[6] which is very important for the cohesion of muscles and for movement. Indeed Myosin forms filament, and when Myosin filaments associate with Actin and consume ATP it produces muscle movement.

Related disease

If the quantity of myosin is not well regulated in the human body, it could trigger many muscle related illnesses^[7], especially when there is too much myostatin, as heart disease, liver disease..

We can focus on the example of COPD (Chronic Obstructive Pulmonary Disease) which is a lunch disease. People suffering from this disease have difficulties to breathe because of an obstruction of airflow ^[7] . Their muscles are not strong enough to help them to breathe the right way and it is called pulmonary cachexia. This disease is also characterized by many muscle complications into the whole body, including a global reduction of muscle mass. It has been proven that a high rate of myostatin quantity in human body can promote this disease. Myostatin has also a role in many metabolisms as in blood glucose^[7]: indeed, the more myostatin you have, the more resistant to insulin you are. This could be link with Type 2 diabetes and so obesity because it is an inducer of Phosphotyrosine Interaction Domain containing 1 (PID1) protein [1] in human muscle cells. Indeed, this protein is known for its role into insulin resistance development.

A way to cure

However, myostatin can also be a way to cure some disease:

If myostatin action is inhibited, researchers have noticed that muscular mass increases ^[4][5].Indeed, myostatin and particularly its inhibition can be a solution to cure muscle atrophy disease: let’s focus on the example of OPMD ^[8], oculopharyngeal muscular dystrophy: This disease involves that the muscles affected show increased fibrosis and atrophy.This is a late-onset disease, affecting 1 people over 80000. It is characterized by dysphagia and ptosis but also limb weakness when the disease is at a very advanced stage. Researcher have noticed that the inhibition of myostatin, increased the muscle quantity and so it help to reduce the symptoms of OPMD. In this case, a monoclonal antibiotic is injected to mice during 10 weeks and the results show that muscle strength and muscle fiber diameter increased and the expression of the markers of muscle fibrosis reduced. However, myostatin does not cure the disease because there was no change in intranuclear inclusion density which is a characteristic of OPMD spread, so, it only treats the symptom. In other cases, it is also possible to introduce follistatin ^[9] to block myostatin because they will form a complex and so it will stop myostatin actions.

Relevance

Structural highlights

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