An Alternative Approach to Myostatin Inhibition to Increase Muscle Growth

Today, I'll point out a group that is working on a novel approach to myostatin inhibition in humans. Myostatin is a part of the regulatory system for muscle growth. Its role is to suppresses muscle growth, and thus lowered levels of myostatin result in less fat and more muscle in a variety of mammalian species, including our own. Complete removal of myostatin via genetic engineering or breakage through rare natural mutation has resulted in very heavily muscled mice, dogs, cows, and even a few people. The technical name for the outcome is myostatin-related muscle hypertrophy. There are no obvious downsides - which doesn't mean they there are absolutely no issues, but if they do exist, then they are largely subtle and long-term problems.

Given this, there is considerable interest in building therapies based on myostatin inhibition. Quite aside from the potential market for human enhancement, satisfying the desire for muscles without the need to work for those muscles, therapies of this type should help to compensate somewhat for sarcopenia, the characteristic age-related loss of muscle mass and muscle function. Not all of that loss relates to a simple lack of muscle tissue, but where it does, adjusting the regulator of muscle growth could be useful. To date, researchers have trialed the use of antibodies to reduce the amount of myostatin in circulation. This appears successful, though to a much lesser degree than genetic loss of myostatin. This is to be expected, and is usually the case when comparing genetic alterations to inhibition of proteins produced from the genetic blueprint - the inhibition only removes or suppresses a portion of the protein.

Other groups are looking ahead to human gene therapies to either disable myostatin or increase levels of follistatin, the natural inhibitor of myostatin. Follistatin gene therapy in mice produces a similar level of muscle growth as myostatin knockout, and was the approach pursued by BioViva Sciences when Elizabeth Parrish underwent gene therapy as a proof of concept and wake up call for the world. I think in general that the current delivery systems for gene therapy are not yet good enough or cheap enough to merit widespread use: they don't edit the genome in enough cells, and especially in the stem cell populations that would be needed to produce a life-long effect. That will likely change soon enough, however, as many researchers are working on the problem.

The notes below cover an alternative and more sophisticated inhibitory approach for myostatin that is presently under development at Scholar Rock - that this material is out there now has a lot to do with there being a company involved, and one that has just raised a sizable amount of funding. That tends to be how things work in the attention economy: always consider cui bono, though the useful result of a spread of knowledge also occurs as a side-effect. Instead of destroying, binding, or otherwise globally interfering with myostatin molecules, here the researchers involved suppress the activation of those molecules. A better understanding of how myostatin functions as a regulator shows that it spends much of its time inactive, and that the system of activation can be constructively interfered with in a number of ways. While this approach should be more selective, time - and forthcoming human trials - will tell as to whether it is better or worse than the more standard approaches to inhibition of a specific protein when it comes to producing additional muscle.

Scientists elucidate molecular basis of myostatin activation, key process in muscle health

Myostatin (also known as GDF8) is a key signaling protein that contributes to the regulation of muscle mass and function. Initially produced by muscle in a latent inactive form, myostatin can be activated under certain conditions by sequential enzymatic steps. For the first time, the new study provides an understanding at the molecular level of the structural changes that take place in the protein during this activation process, and the central role of the tolloid enzyme in generating active myostatin. Insight into the activation mechanism of myostatin and other related proteins is central to the drug discovery platform established at Scholar Rock for the development of novel therapies for the treatment of many severe diseases.

"Deploying deep structural understanding of growth factors and their activation is opening a profound new way to intervene in human disease. SRK-015, our clinical candidate for the treatment of muscle atrophy and wasting disorders, exemplifies the strong potential of targeting specific structural states of myostatin with the objective of providing superior therapeutic outcomes."

The proprietary therapeutic antibody, SRK-015, was discovered and designed to selectively and locally target the latent form of myostatin with the ability to specifically block its intramuscular activation. In a variety of preclinical models of muscle atrophy, SRK-015 has demonstrated improvement in muscle function. SRK-015 is initially being developed for the improvement of muscle strength and function in patients with Spinal Muscular Atrophy (SMA) with the treatment of additional neuromuscular diseases to follow.

SRK-015 for Spinal Muscular Atrophy (SMA)

SRK-015 uniquely targets the latent form of myostatin, specifically blocking its activation in muscle. Inhibiting the supracellular activation of myostatin, rather than the traditional approach of blocking already activated, mature myostatin or the myostatin receptor, avoids blocking the activity of other closely-related members of the TGFβ superfamily that may lead to undesirable side effects. Scholar Rock is actively working to advance SRK-015 into clinical trials, which are anticipated to commence in mid-2018. We intend to develop SRK-015 in combination with therapies aimed at correcting the underlying genetic defect in SMA and as monotherapy in patients with certain subtypes of SMA.

Tolloid cleavage activates latent GDF8 by priming the pro-complex for dissociation

Growth differentiation factor 8 (GDF8)/Myostatin is a latent TGF-β family member that potently inhibits skeletal muscle growth. Here, we compared the conformation and dynamics of precursor, latent, and Tolloid-cleaved GDF8 pro-complexes to understand structural mechanisms underlying latency and activation of GDF8. Why some TGF-β family members are active and others are latent as procomplexes is incompletely understood. Here, we ask why GDF8 is latent, and what changes when it becomes activated.

GDF8 and its close relative GDF11 are activated by BMP1/Tolloid (TLD) metalloprotease-mediated cleavage of the prodomain between the straitjacket elements and the arm domain. Tolloid-like protein 2 (TLL2), used in this paper, is among the most active on GDF8 of the four TLD proteases found in mammals, and is the only TLD protease expressed in muscle. While TLD cleavage clearly activates signaling by GDF8, whether the two prodomain fragments rapidly dissociate from GDF8 after cleavage, or remain associated with GDF8 in a "primed" state, is not known. Here, we compare pro-GDF8, the state prior to PC cleavage; latent GDF8, the state after PC cleavage; and primed GDF8, a state after TLD cleavage in which we found the persistence of substantial prodomain-GDF8 association.

Comments

It is still an antibody approach (from my brief read through). So will still be expensive and manufactured by big pharma. Plasmids for in vivo production of antibodies are expensive, but perhaps a (disruptive) technology like LPS free Clear coli could bring their price down?

Posted by: Jim at January 24th, 2018 10:14 AM

for example i'm a 58 year old men and had a few years ago (2012) a heart-infarctus afther that i've lost a lot of muscle and strenght could it e possible with a myostatineblokker to gain the los en repairing the heart, because this also is a musle ?

Posted by: Michel Vranckx at August 9th, 2019 12:35 AM

Let me know when this makes it to the market! Haha

Posted by: Kyle at February 21st, 2020 6:49 AM

Very informative...

Posted by: Sanna at February 22nd, 2021 2:07 PM
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