Myostatin

[Michael Scally MD]

[OA] [Mice] Targeting Myostatin/Activin A Protects Against Skeletal Muscle and Bone Loss During Spaceflight

Among the major health challenges for astronauts during prolonged space travel are loss of muscle mass and loss of bone mass. Here, we investigated the effects of targeting the signaling pathway mediated by the secreted signaling molecules, myostatin and activin A, in mice sent to the International Space Station.

We show that targeting this signaling pathway has significant beneficial effects in protecting against both muscle and bone loss in microgravity, suggesting that this strategy may be effective in preventing or treating muscle and bone loss not only in astronauts on prolonged missions but also in people with disuse atrophy on Earth, such as in older adults or in individuals who are bedridden or wheelchair-bound from illness.

Se-Jin Lee el al., "Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight," PNAS (2020). www.pnas.org/cgi/doi/10.1073/pnas.2014716117

Among the physiological consequences of extended spaceflight are loss of skeletal muscle and bone mass. One signaling pathway that plays an important role in maintaining muscle and bone homeostasis is that regulated by the secreted signaling proteins, myostatin (MSTN) and activin A.

Here, we used both genetic and pharmacological approaches to investigate the effect of targeting MSTN/activin A signaling in mice that were sent to the International Space Station. Wild type mice lost significant muscle and bone mass during the 33 d spent in microgravity.

Muscle weights of Mstn −/− mice, which are about twice those of wild type mice, were largely maintained during spaceflight. Systemic inhibition of MSTN/activin A signaling using a soluble form of the activin type IIB receptor (ACVR2B), which can bind each of these ligands, led to dramatic increases in both muscle and bone mass, with effects being comparable in ground and flight mice.

Exposure to microgravity and treatment with the soluble receptor each led to alterations in numerous signaling pathways, which were reflected in changes in levels of key signaling components in the blood as well as their RNA expression levels in muscle and bone.

These findings have implications for therapeutic strategies to combat the concomitant muscle and bone loss occurring in people afflicted with disuse atrophy on Earth as well as in astronauts in space, especially during prolonged missions.

 

[Michael Scally MD]

Myostatin Inhibitors: Panacea or Predicament for Musculoskeletal Disorders?

Myostatin, also known as growth differentiation factor 8 (GDF8), is a transforming growth factor-β (TGF-β) family member that functions to limit skeletal muscle growth. Accordingly, loss-of-function mutations in myostatin result in a dramatic increase in muscle mass in humans and various animals, while its overexpression leads to severe muscle atrophy. Myostatin also exerts a significant effect on bone metabolism, as demonstrated by enhanced bone mineral density and bone regeneration in myostatin null mice.

The identification of myostatin as a negative regulator of muscle and bone mass has sparked an enormous interest in developing myostatin inhibitors as therapeutic agents for treating a variety of clinical conditions associated with musculoskeletal disorders. As a result, various myostatin-targeting strategies involving antibodies, myostatin propeptides, soluble receptors, and endogenous antagonists have been generated, and many of them have progressed to clinical trials.

Importantly, most myostatin inhibitors also repress the activities of other closely related TGF-β family members including GDF11, activins, and bone morphogenetic proteins (BMPs), increasing the potential for unwanted side effects, such as vascular side effects through inhibition of BMP 9/10 and bone weakness induced by follistatin through antagonizing several TGF-β family members.

Therefore, a careful distinction between targets that may enhance the efficacy of an agent and those that may cause adverse effects is required with the improvement of the target specificity. In this review, we discuss the current understanding of the endogenous function of myostatin, and provide an overview of clinical trial outcomes from different myostatin inhibitors.

Suh J, Lee YS. Myostatin Inhibitors: Panacea or Predicament for Musculoskeletal Disorders?. J Bone Metab. 2020;27(3):151-165. doi:10.11005/jbm.2020.27.3.151 Myostatin Inhibitors: Panacea or Predicament for Musculoskeletal Disorders?

 

[Michael Scally MD]

[OA] [Mice] Novel Myostatin-Specific Antibody Enhances Muscle Strength in Muscle Disease Models

Myostatin, a member of the transforming growth factor-b superfamily, is an attractive target for muscle disease therapy because of its role as a negative regulator of muscle growth and strength. Here, we describe a novel antibody therapeutic approach that maximizes the potential of myostatin-targeted therapy.

We generated an antibody, GYM329, that specifically binds the latent form of myostatin and inhibits its activation. Additionally, via “sweeping antibody technology”, GYM329 reduces or “sweeps” myostatin in the muscle and plasma. Compared with conventional anti-myostatin agents, GYM329 and its surrogate antibody exhibit superior muscle strength-improvement effects in three different mouse disease models.

We also demonstrate that the superior efficacy of GYM329 is due to its myostatin specificity and sweeping capability. Furthermore, we show that a GYM329 surrogate increases muscle mass in normal cynomolgus monkeys without any obvious toxicity. Our findings indicate the potential of GYM329 to improve muscle strength in patients with muscular disorders.

Muramatsu H, Kuramochi T, Katada H, et al. Novel Myostatin-Specific Antibody Enhances Muscle Strength in Muscle Disease Models. Research Square. Novel Myostatin-Specific Antibody Enhances Muscle Strength in Muscle Disease Models

 

[Michael Scally MD]

[OA] Blocking Extracellular Activation of Myostatin As A Strategy for Treating Muscle Wasting

Many growth factors are intimately bound to the extracellular matrix, with regulated processing and release leading to cellular stimulation. Myostatin and GDF11 are closely related members of the TGFβ family whose activation requires two proteolytic cleavages to release the growth factor from the prodomain.

Specific modulation of myostatin and GDF11 activity by targeting growth factor-receptor interactions has traditionally been challenging. Here we demonstrate that a novel strategy for blocking myostatin and GDF11, inhibition of growth factor release, specifically and potently inhibits signaling both in vitro and in vivo.

We developed human monoclonal antibodies that selectively bind the myostatin and GDF11 precursor forms, including a subset that inhibit myostatin proteolytic activation and prevent muscle atrophy in vivo. The most potent myostatin activation-blocking antibodies promoted robust muscle growth and resulted in significant gains in muscle performance in healthy mice.

Altogether, we show that blocking the extracellular activation of growth factors is a potent method for preventing signaling, serving as proof of concept for a novel therapeutic strategy that can be applied to other members of the TGFβ family of growth factors.

Pirruccello-Straub, M., Jackson, J., Wawersik, S. et al. Blocking extracellular activation of myostatin as a strategy for treating muscle wasting. Sci Rep 8, 2292 (2018). https://doi.org/10.1038/s41598-018-20524-9

 

[Michael Scally MD]

[OA] The Failed Clinical Story of Myostatin Inhibitors against Duchenne Muscular Dystrophy: Exploring the Biology behind the Battle

Myostatin inhibition therapy has held much promise for the treatment of muscle wasting disorders. This is particularly true for the fatal myopathy, Duchenne Muscular Dystrophy (DMD). Following on from promising pre-clinical data in dystrophin-deficient mice and dogs, several clinical trials were initiated in DMD patients using different modality myostatin inhibition therapies. All failed to show modification of disease course as dictated by the primary and secondary outcome measures selected: the myostatin inhibition story, thus far, is a failed clinical story.

These trials have recently been extensively reviewed and reasons why pre-clinical data collected in animal models have failed to translate into clinical benefit to patients have been purported. However, the biological mechanisms underlying translational failure need to be examined to ensure future myostatin inhibitor development endeavors do not meet with the same fate. Here, we explore the biology which could explain the failed translation of myostatin inhibitors in the treatment of DMD.

Rybalka E, Timpani CA, Debruin DA, et al. The Failed Clinical Story of Myostatin Inhibitors against Duchenne Muscular Dystrophy: Exploring the Biology behind the Battle. Cells. 2020 Dec 10;9(12):E2657. doi: 10.3390/cells9122657. PMID: 33322031. https://www.mdpi.com/2073-4409/9/12/2657/htm

 

[Hank81]

I think I'm going to experiment with folistatin

The peptide sucks, YK-11 is much better cost effective.

 

[malfeasance]

Re: When Will We Have a SAFE & EFFECTIVE Myostatin Inhibitor in the Future?




A healthy woman who was a former professional athlete gave birth to a son after a normal pregnancy. The identity of the child's father was not revealed. The child's birth weight was in the 75th percentile. He appeared extraordinarily muscular, with protruding muscles in his thighs and upper arms. With the exception of increased tendon reflexes, the physical examination was normal. Hypoglycemia and increased levels of testosterone and insulin-like growth factor I were excluded. Muscular hypertrophy was verified by ultrasonography when the infant was six days of age. The stimulus-induced myoclonus gradually subsided after two months. The child's motor and mental development has been normal. Now, at 4.5 years of age, he continues to have increased muscle bulk and strength, and he is able to hold two 3-kg dumbbells in horizontal suspension with his arms extended.


Schuelke M, Wagner KR, Stolz LE, et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 2004;350(26):2682-8. http://www.nejm.org/doi/full/10.1056/NEJMoa040933#t=article

McNally EM. Powerful genes--myostatin regulation of human muscle mass. N Engl J Med 2004;350(26):2642-4. http://www.nejm.org/doi/full/10.1056/NEJMp048124#t=article

This kid is an adult in his twenties now.

Maybe he is competing?

 

[Michael Scally MD]

[OA] Blocking Myostatin: Muscle Mass Equals Muscle Strength?

Myostatin also known as growth differentiation factor 8 (GDF‐8) has been of major interest in the cachexia/sarcopenia/muscle wasting community since its discovery by McPherron et al. in 1997. …

In this issue of the Journal of Cachexia, Sarcopenia and Muscle, Rooks et al. describe the safety profile, pharmacokinetics, and pharmacodynamics of the human monoclonal antibody bimagrumab, which blocks the activin type II receptors, in healthy older and obese adults. Bimagrumab was safe and well tolerated, and the pharmacokinetics were similar in both studies. https://onlinelibrary.wiley.com/doi/full/10.1002/jcsm.12205

A rapid increase of lean body mass and thigh muscle volume was observed, while fat mass decreased. In the high dose group (30 mg/kg, single iv. infusion), the increase of lean mass was maintained over 4 weeks, while the 3 mg/kg dose did not. Unfortunately, no improvement of muscle strength/function was observed, but this may be due to short study duration and single dosing of bimagrumab.

In general, there seems to be no direct relationship between muscle mass and strength,31 making the development of myostatin pathway targeting therapeutics very challenging at best.

Anker MS, von Haehling S, Springer J. Blocking myostatin: muscle mass equals muscle strength? J Cachexia Sarcopenia Muscle. 2020 Dec;11(6):1396-1398. doi: 10.1002/jcsm.12647. PMID: 33340286. https://onlinelibrary.wiley.com/doi/10.1002/jcsm.12647

 

[Michael Scally MD]

[OA] Blocking Myostatin: Muscle Mass Equals Muscle Strength?

Myostatin also known as growth differentiation factor 8 (GDF‐8) has been of major interest in the cachexia/sarcopenia/muscle wasting community since its discovery by McPherron et al. in 1997. …

In this issue of the Journal of Cachexia, Sarcopenia and Muscle, Rooks et al. describe the safety profile, pharmacokinetics, and pharmacodynamics of the human monoclonal antibody bimagrumab, which blocks the activin type II receptors, in healthy older and obese adults. Bimagrumab was safe and well tolerated, and the pharmacokinetics were similar in both studies. https://onlinelibrary.wiley.com/doi/full/10.1002/jcsm.12205

A rapid increase of lean body mass and thigh muscle volume was observed, while fat mass decreased. In the high dose group (30 mg/kg, single iv. infusion), the increase of lean mass was maintained over 4 weeks, while the 3 mg/kg dose did not. Unfortunately, no improvement of muscle strength/function was observed, but this may be due to short study duration and single dosing of bimagrumab.

In general, there seems to be no direct relationship between muscle mass and strength,31 making the development of myostatin pathway targeting therapeutics very challenging at best.

Anker MS, von Haehling S, Springer J. Blocking myostatin: muscle mass equals muscle strength? J Cachexia Sarcopenia Muscle. 2020 Dec;11(6):1396-1398. doi: 10.1002/jcsm.12647. PMID: 33340286. https://onlinelibrary.wiley.com/doi/10.1002/jcsm.12647

[OA] Effect of Bimagrumab on Thigh Muscle Volume and Composition in Men with Casting-Induced Atrophy

Background: Patients experiencing disuse atrophy report acute loss of skeletal muscle mass which subsequently leads to loss of strength and physical capacity. In such patients, especially the elderly, complete recovery remains a challenge even with improved nutrition and resistance exercise.

This study aimed to explore the clinical potential of bimagrumab, a human monoclonal antibody targeting the activin type II receptor, for the recovery of skeletal muscle volume from disuse atrophy using an experimental model of lower extremity immobilization.

Methods: In this double-blind, placebo-controlled trial, healthy young men (n = 24; mean age, 24.1 years) were placed in a full-length cast of one of the lower extremities for 2 weeks to induce disuse atrophy. After cast removal, subjects were randomized to receive a single intravenous (i.v.) dose of either bimagrumab 30 mg/kg (n = 15) or placebo (n = 9) and were followed for 12 weeks. Changes in thigh muscle volume (TMV) and inter-muscular adipose tissue (IMAT) and subcutaneous adipose tissue (SCAT) of the thigh, maximum voluntary knee extension strength, and safety were assessed throughout the 12 week study.

Results: Casting resulted in an average TMV loss of -4.8% and comparable increases in IMAT and SCAT volumes. Bimagrumab 30 mg/kg i.v. resulted in a rapid increase in TMV at 2 weeks following cast removal and a +5.1% increase above pre-cast levels at 12 weeks. In comparison, TMV returned to pre-cast level at 12 weeks (-0.1%) in the placebo group.

The increased adiposity of the casted leg was sustained in the placebo group and decreased substantially in the bimagrumab group at Week 12 (IMAT: -6.6%, SCAT: -3.5%). Knee extension strength decreased by ~25% in the casted leg for all subjects and returned to pre-cast levels within 6 weeks after cast removal in both treatment arms. Bimagrumab was well tolerated with no serious or severe adverse events reported during the study.

Conclusions: A single dose of bimagrumab 30 mg/kg i.v. safely accelerated the recovery of TMV and reversal of accumulated IMAT following 2 weeks in a joint-immobilizing cast.

Rooks DS, Laurent D, Praestgaard J, Rasmussen S, Bartlett M, Tankó LB. Effect of bimagrumab on thigh muscle volume and composition in men with casting-induced atrophy. J Cachexia Sarcopenia Muscle. 2017 Oct;8(5):727-734. doi: 10.1002/jcsm.12205. Epub 2017 Sep 14. PMID: 28905498; PMCID: PMC5659065. https://onlinelibrary.wiley.com/doi/full/10.1002/jcsm.12205

 

[Michael Scally MD]

[OA] Novel Myostatin-Specific Antibody Enhances Muscle Strength In Muscle Disease Models

Myostatin, a member of the transforming growth factor-β superfamily, is an attractive target for muscle disease therapy because of its role as a negative regulator of muscle growth and strength. Here, we describe a novel antibody therapeutic approach that maximizes the potential of myostatin-targeted therapy.

We generated an antibody, GYM329, that specifically binds the latent form of myostatin and inhibits its activation. Additionally, via "sweeping antibody technology", GYM329 reduces or "sweeps" myostatin in the muscle and plasma. Compared with conventional anti-myostatin agents, GYM329 and its surrogate antibody exhibit superior muscle strength-improvement effects in three different mouse disease models.

We also demonstrate that the superior efficacy of GYM329 is due to its myostatin specificity and sweeping capability. Furthermore, we show that a GYM329 surrogate increases muscle mass in normal cynomolgus monkeys without any obvious toxicity. Our findings indicate the potential of GYM329 to improve muscle strength in patients with muscular disorders.

Muramatsu H, Kuramochi T, Katada H, et al. Novel myostatin-specific antibody enhances muscle strength in muscle disease models. Sci Rep. 2021 Jan 25;11(1):2160. doi: 10.1038/s41598-021-81669-8. PMID: 33495503. https://www.nature.com/articles/s41598-021-81669-8

 

[malfeasance]

We need some GYM329 (I like how the name has "gym" in it) to add to long cycles!

 

[FR0Z3N_B0MB3RRR]

I remember having read something like that born whit a myostatin inhibition is a totally different thing, compared to myostatin inhibition after body is formed ... something related to cells proliferation that without myostatin take one route, totally different from the one the body had taken when myostatin is present pre birth..

Hope no one won’t ever develop such a tool... don’t wanna see fuckin rich lazy ass motherfuckers showing up with Markus Ruhl’s body