Myostatin

[Michael Scally MD]

[2004] Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child

[Has there been additional follow-up on the child?]

The function of myostatin appears to be conserved across species, since mutations in the myostatin gene have been shown to be responsible for the “double-muscling” phenotype in cattle. The phenotypes of mice and cattle lacking myostatin and the high degree of sequence conservation of the predicted myostatin protein in many mammalian species have raised the possibility that myostatin may help regulate muscle growth in humans.

We report the identification of a myostatin mutation in a child with muscle hypertrophy, thereby providing strong evidence that myostatin does play an important role in regulating muscle mass in humans.

…

These results strongly indicate that our patient has a loss-of-function mutation in the myostatin gene, thus suggesting that the inactivation of myostatin has similar effects in humans, mice, and cattle.

So far, we have not observed any health problems in the patient. Since myostatin is also expressed in the heart, we have closely monitored our patient's cardiac function but have not yet detected any signs of cardiomyopathy or a conduction disturbance.

However, at 4.5 years of age, our patient is still too young for such abnormalities to be ruled out definitively. Our results suggest the possibility that muscle bulk and strength could be therapeutically increased by the inactivation of myostatin in patients with muscle-wasting conditions.

Schuelke M, Wagner KR, Stolz LE, et al. Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child. New England Journal of Medicine 2004;350(26):2682-8. http://www.nejm.org/doi/full/10.1056/NEJMoa040933

 

[Michael Scally MD]

Becker C, Lord SR, Studenski SA, et al. Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial. Lancet Diabetes Endocrinol. https://www.sciencedirect.com/science/article/pii/S2213858715002983

BACKGROUND: Myostatin inhibits skeletal muscle growth. The humanised monoclonal antibody LY2495655 (LY) binds and neutralises myostatin. We aimed to test whether LY increases appendicular lean body mass (aLBM) and improves physical performance in older individuals who have had recent falls and low muscle strength and power.

METHODS: In this proof-of-concept, randomised, placebo-controlled, double-blind, parallel, multicentre, phase 2 study, we recruited patients aged 75 years or older who had fallen in the past year from 21 investigator sites across Argentina, Australia, France, Germany, Sweden, and the USA. Eligible patients had low performance on hand grip strength and chair rise tests, tested with the procedure described by Guralnik and colleagues. Participants were stratified by country, age, hand grip strength, and performance on the chair rise test, and were randomly assigned (1:1) by a computer-generated random sequence to receive subcutaneous injections of placebo or 315 mg LY at weeks 0 (randomisation visit), 4, 8, 12, 16, and 20, followed by 16 weeks observation. The primary outcome was change in aLBM from baseline to 24 weeks. We measured physical performance as secondary outcomes (four-step stair climbing time, usual gait speed, and time to rise five times from a chair without arms, or with arms for participants unable to do it without arms) and exploratory outcomes (12-step stair climbing test, 6-min walking distance, fast gait speed, hand grip strength, and isometric leg extension strength). Efficacy analyses included all randomly assigned patients who received at least one dose and had a baseline and at least one subsequent measure. The primary analysis and all other tests of treatment effect (except physical performance tests) were done at a two-sided alpha level of 0.05. Tests of treatment effect on physical performance tests were done at a pre-specified two-sided alpha level of 0.1. This trial is registered with ClinicalTrials.gov, number NCT01604408.

FINDINGS: Between June 19, 2012, and Dec 12, 2013, we screened 365 patients. 99 were randomly assigned to receive placebo and 102 to receive LY. Treatment was completed in 85 (86%) of patients given placebo and in 82 (80%) given LY. At 24 weeks, the least-squares mean change in aLBM was -0.123 kg (95% CI -0.287 to 0.040) in the placebo group and 0.303 kg (0.135 to 0.470) in the LY group, a difference of 0.43 kg (95% CI 0.192 to 0.660; p<0.0001). Stair climbing time (four-step and 12-step tests), chair rise with arms, and fast gait speed improved significantly from baseline to week 24 with differences between LY and placebo of respectively -0.46 s (p=0.093), -1.28 s (p=0.011), -4.15 s (p=0.054), and 0.05 m/s (p=0.088). No effect was detected for other performance-based measures. Injection site reactions were recorded in nine (9%) patients given placebo and in 31 (30%) patients given LY (p<0.0001), and were generally mild, and led to treatment discontinuation in two patients given LY.

INTERPRETATION: Our findings show LY treatment increases lean mass and might improve functional measures of muscle power. Although additional studies are needed to confirm these results, our data suggest LY should be tested for its potential ability to reduce the risk of falls or physical dependency in older weak fallers.

FUNDING: Eli Lilly and Company.

 

[Michael Scally MD]

[Open Access] Connecting Myokines and Metabolism

The concept that skeletal muscle secretes humoral factors that actively communicate with other organs was proposed many years ago. They used the term "myokines" to describe cytokines and other peptides expressed and released by muscle cells.

Myokines are proposed to play important roles in mediating the beneficial effects of skeletal muscle mass and exercise on health. Myokines have been implicated in the pathogenesis of obesity, substrate oxidation, lipid partitioning, insulin sensitivity, and inflammation.

Skeletal muscle is the largest organ of the body in non-obese individuals and is now considered to be an endocrine organ. Hormones (myokines) secreted by skeletal muscle mediate communications between muscle and liver, adipose tissue, brain, and other organs.

Myokines affect muscle mass and myofiber switching, and have profound effects on glucose and lipid metabolism and inflammation, thus contributing to energy homeostasis and the pathogenesis of obesity, diabetes, and other diseases.

While the list of putative myokines keeps growing, the specific physiological and pathological effects of these molecules are poorly understood. Important questions that need to be answered for a presumed myokine include whether skeletal muscle is the main or only source, how the local and systemic concentrations of the myokine are regulated, whether there are biological differences among species, and what specific signaling mechanisms mediate the biological effects of the myokine in various organs.

A better understanding of the actions of myokines may identify novel therapies for obesity, diabetes, cardiovascular diseases, cancer, and other diseases known to be improved by exercise.

This review highlights the biological actions of myostatin and other myokines that regulate skeletal muscle mass and metabolism via autocrine, paracrine, and endocrine mechanisms and to provide an assessment of their potential as therapeutic targets.

Ahima RS, Park HK. Connecting Myokines and Metabolism. Endocrinology and Metabolism 2015;30:235. http://synapse.koreamed.org/DOIx.php?id=10.3803/EnM.2015.30.3.235

 

[Michael Scally MD]

Highlights
· Myostatin null mice display greater functional decline at middle age than wild-type controls.
· Myostatin null mice exhibit misshapen of ankle joint structure, featured with osteoarthritis-like symptom at middle age.
· Myostatin null mice display altered gene expression at tendon-bone insertion region in favor of bone formation, starting at neonatal age and maintaining beyond middle age.

Guo W, Miller AD, Pencina K, et al. Joint dysfunction and functional decline in middle age myostatin null mice. Bone. https://www.sciencedirect.com/science/article/pii/S8756328215003968

Since its discovery as a potent inhibitor for muscle development, myostatin has been actively pursued as a drug target for age- and disease-related muscle loss.

However, potential adverse effects of long-term myostatin deficiency have not been thoroughly investigated.

We report herein that male myostatin null mice (mstn-/-), in spite of their greater muscle mass compared to wild-type (wt) mice, displayed more significant functional decline from young (3-6months) to middle age (12-15months) than age-matched wt mice, measured as gripping strength and treadmill endurance.

Mstn-/- mice displayed markedly restricted ankle mobility and degenerative changes of the ankle joints, including disorganization of bone, tendon and peri-articular connective tissue, as well as synovial thickening with inflammatory cell infiltration.

Messenger RNA expression of several pro-osteogenic genes was higher in the Achilles tendon-bone insertion in mstn-/- mice than wt mice, even at the neonatal age.

At middle age, higher plasma concentrations of growth factors characteristic of excessive bone remodeling were found in mstn-/- mice than wt controls.

These data collectively indicate that myostatin may play an important role in maintaining ankle and wrist joint health, possibly through negative regulation of the pro-osteogenic WNT/BMP pathway.

 

[Michael Scally MD]

Kong WH, Sung DK, Kim H, et al. Self-adjuvanted hyaluronate - antigenic peptide conjugate for transdermal treatment of muscular dystrophy. Biomaterials 2016;81:93-103. Elsevier: Article Locator

Duchenne's muscular dystrophy (DMD) is a neuromuscular disorder accompanied with muscle weakness and wasting.

Since myostatin was reported to be a key regulator of muscle wasting, myostatin inhibitors have been investigated as therapeutic candidates for the treatment of muscular diseases.

Here, we report an antigenic peptide of myostatin fragment (MstnF) conjugated to hyaluronate (HA) with a low molecular weight (MW, 17 kDa) for transdermal immunotherapy of DMD.

Facilitating the transdermal delivery, the low MW HA showed a boosting effect on the immunization of MstnF possibly by engaging both toll-like receptors and cluster of differentiation 44 (CD44).

In vivo two-photon microscopy clearly visualized the effective transdermal penetration of HA-MstnF conjugates into deep intact skin layers.

The transdermal immunization of mdx mice significantly increased antibody titers against myostatin.

Furthermore, the mdx mice immunized with HA-MstnF conjugates resulted in statistically significant improvement in the biochemical and pathological status of skeletal musculature as well as functional behaviors.

 

[Demondosage]

it's called Follistatin and it's been out awhile now. I'm not talking cheap fake stuff from research sites, I'm talking about REAL follistatin that is only available from a laboratory. The cost is about $5,000 for 3-4 weeks of it. One of the biggest indicators of legit Follistatin usage is the overdevelopment of the quadriceps, this is the area that responds the most to follistatin use.

 

[Michael Scally MD]

Myostatin: Expanding Horizons

Myostatin is a secreted growth and differentiation factor that belongs to the TGF-beta superfamily.

Myostatin is predominantly synthesized and expressed in skeletal muscle and thus exerts a huge impact on muscle growth and function.

In keeping with its negative role in myogenesis, myostatin expression is tightly regulated at several levels including epigenetic, transcriptional, post-transcriptional, and post-translational.

New revelations regarding myostatin regulation also offer mechanisms that could be exploited for developing myostatin antagonists.

Increasingly, it is becoming clearer that besides its conventional role in muscle, myostatin plays a critical role in metabolism.

Hence, molecular mechanisms by which myostatin regulates several key metabolic processes need to be further explored.

Sharma M, McFarlane C, Kambadur R, Kukreti H, Bonala S, et al. Myostatin: Expanding horizons. IUBMB Life. Myostatin: Expanding horizons - Sharma - 2015 - IUBMB Life - Wiley Online Library

Summary of Myostatin Function During Muscle Wasting and Insulin Resistance

(a) Increased myostatin levels can promote the development of insulin resistance.

High glucose and palmitate result in transcriptional activation of myostatin through the action of carbohydrate-responsive element-binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP1c), respectively.

Elevated myostatin levels lead to increased expression of Casitas B-lineage lymphoma b (Cblb) and phosphotyrosine interaction domain containing 1 (PID1) through Smad3- and NFjB-dependent signaling mechanisms respectively, which in turn target and repress insulin signaling.

Impaired insulin signaling results in reduced glucose uptake and the eventual development of insulin resistance.

(b) Myostatin promotes the development of skeletal muscle wasting. Epigenetic and genetic factors lead to increased levels of myostatin during skeletal muscle wasting.

Increased levels of myostatin result in activation of canonical Smad3 signaling and increased expression of Forkhead Box O (FoxO) transcription factors.

Inhibition of pAkt by myostatin promotes the activation and subsequent nuclear translocation of FoxO transcription factors to increase the expression of downstream target genes.

Increased FoxO activation results in increased expression of the ubiquitin E3 ligases Atrogin-1 and MuRF1, enhanced ubiquitinproteasome pathway (UPP)-mediated protein degradation and muscle wasting.

Myostatin has further been shown to increase the expression of miR-1, which inhibits HSP70 and subsequently reduces pAkt levels leading to increased FoxO, Atrogin-1 and MuRF1 expression and the development of skeletal muscle wasting.

 

[BIGGUNS]

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

its already out there , only used on cattle , but it will find its way into the main stream soon or later

 

[Michael Scally MD]

Inhibition of the Myostatin/Smad Signaling Pathway by Short Decorin-Derived Peptides

Highlight

• Decorin peptides DCN48-71 and 42-65 bind to myostatin in a zinc-dependent manner.
• The decorin peptides can inhibit the myostatin induced activation of Smad2/3.
• Other members of the TGF-β family are not inhibited by the DCN peptides.

Myostatin, also known as growth differentiation factor 8, is a member of the transforming growth factor-beta superfamily that has been shown to play a key role in the regulation of the skeletal muscle mass. Indeed, while myostatin deletion or loss of function induces muscle hypertrophy, its overexpression or systemic administration causes muscle atrophy.

Since myostatin blockade is effective in increasing skeletal muscle mass, myostatin inhibitors have been actively sought after. Decorin, a member of the small leucine-rich proteoglycan family is a metalloprotein that was previously shown to bind and inactivate myostatin in a zinc-dependent manner. Furthermore, the myostatin-binding site has been shown to be located in the decorin N-terminal domain.

In the present study, we investigated the anti-myostatin activity of short and soluble fragments of decorin. Our results indicate that the murine decorin peptides DCN48-71 and 42-65 are sufficient for inactivating myostatin in vitro. Moreover, we show that the interaction of mDCN48-71 to myostatin is strictly zinc-dependent.

Binding of myostatin to activin type II receptor results in the phosphorylation of Smad2/3. Addition of the decorin peptide 48-71 decreased in a dose-dependent manner the myostatin-induced phosphorylation of Smad2 demonstrating thereby that the peptide inhibits the activation of the Smad signaling pathway.

Finally, we found that mDCN48-71 displays a specificity towards myostatin, since it does not inhibit other members of the transforming growth factor-beta family.

El Shafey N, Guesnon M, Simon F, et al. Inhibition of the myostatin/Smad signaling pathway by short decorin-derived peptides. Exp Cell Res. Inhibition of the myostatin/Smad signaling pathway by short decorin-derived peptides

 

[Michael Scally MD]

[Open Access] Anti-Myostatin Antibody Increases Muscle Mass and Strength and Improves Insulin Sensitivity in Old Mice

[Conflict of interest statement: These studies were funded in part by an investigator initiated grant to Kitt Falk Petersena from Atara Biotherapeutics, the manufacturer of ATA 842. Glenn Friedmand and Christopher M. Haqqd are employees of Atara and may own stock in the company. http://www.atarabio.com/ ]

Sarcopenia, or skeletal muscle atrophy, is a debilitating comorbidity of many physiological and pathophysiological processes, including normal aging.

There are no approved therapies for sarcopenia, but the antihypertrophic myokine myostatin is a potential therapeutic target.

Here, we show that treatment of young and old mice with an anti-myostatin antibody (ATA 842) for 4 wk increased muscle mass and muscle strength in both groups.

Furthermore, ATA 842 treatment also increased insulin-stimulated whole body glucose metabolism in old mice, which could be attributed to increased insulin-stimulated skeletal muscle glucose uptake as measured by a hyperinsulinemic-euglycemic clamp.

Taken together, these studies provide support for pharmacological inhibition of myostatin as a potential therapeutic approach for age-related sarcopenia and metabolic disease.

Camporez JG, Petersen MC, Abudukadier A, et al. Anti-myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice. Proc Natl Acad Sci U S A. http://www.pnas.org/content/early/2016/02/04/1525795113.full.pdf

 

[Michael Scally MD]

[Open Access] Nfix Regulates Temporal Progression of Muscle Regeneration through Modulation of Myostatin Expression

Highlights
· Muscle differentiation is delayed in Nfix-null satellite cells in vitro
· Mice lacking Nfix in satellite cells show delayed regeneration upon injury
· Nfix directly regulates Myostatin expression during regeneration
· In vivo silencing of Myostatin rescues the regeneration deficit in Nfix-null mice

Rossi G, Antonini S, Bonfanti C, et al. Nfix Regulates Temporal Progression of Muscle Regeneration through Modulation of Myostatin Expression. Cell Rep. Nfix Regulates Temporal Progression of Muscle Regeneration through Modulation of Myostatin Expression

Nfix belongs to a family of four highly conserved proteins that act as transcriptional activators and/or repressors of cellular and viral genes. We previously showed a pivotal role for Nfix in regulating the transcriptional switch from embryonic to fetal myogenesis. Here, we show that Nfix directly represses the Myostatin promoter, thus controlling the proper timing of satellite cell differentiation and muscle regeneration. Nfix-null mice display delayed regeneration after injury, and this deficit is reversed upon in vivo Myostatin silencing. Conditional deletion of Nfix in satellite cells results in a similar delay in regeneration, confirming the functional requirement for Nfix in satellite cells. Moreover, mice lacking Nfix show reduced myofiber cross sectional area and a predominant slow twitching phenotype. These data define a role for Nfix in postnatal skeletal muscle and unveil a mechanism for Myostatin regulation, thus providing insights into the modulation of its complex signaling pathway.

 

[Michael Scally MD]

Zhao X, Ni W, Chen C, et al. Targeted Editing of Myostatin Gene in Sheep by Transcription Activator-like Effector Nucleases. Asian-Australas J Anim Sci 2016;29(3):413-8. Targeted Editing of Myostatin Gene in Sheep by Transcription Activator-like Effector Nucleases

Myostatin (MSTN) is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Gene knockout of MSTN can result in increasing muscle mass in sheep. The objectives were to investigate whether myostatin gene can be edited in sheep by transcription activator-like effector nucleases (TALENs) in tandem with single-stranded DNA oligonucleotides (ssODNs). We designed a pair of TALENs to target a highly conserved sequence in the coding region of the sheep MSTN gene. The activity of the TALENs was verified by using luciferase single-strand annealing reporter assay in HEK 293T cell line. Co-transfection of TALENs and ssODNs oligonucleotides induced precise gene editing of myostatin gene in sheep primary fibroblasts. MSTN gene-edited cells were successfully used as nuclear donors for generating cloned embryos. TALENs combined with ssDNA oligonucleotides provide a useful approach for precise gene modification in livestock animals.

 

[Michael Scally MD]

Takayama K, Nakamura A, Rentier C, et al. Effect of N-Terminal Acylation on the Activity of Myostatin Inhibitory Peptides. ChemMedChem. Effect of N-Terminal Acylation on the Activity of Myostatin Inhibitory Peptides - Takayama - 2016 - ChemMedChem - Wiley Online Library

Inhibition of myostatin, which negatively regulates skeletal muscle growth, is a promising strategy for the treatment of muscle atrophic disorders, such as muscular dystrophy, cachexia and sarcopenia. Recently, we identified peptide A (H-WRQNTRYSRIEAIKIQILSKLRL-NH2 ), the 23-amino-acid minimum myostatin inhibitory peptide derived from mouse myostatin prodomain, and highlighted the importance of its N-terminal tryptophan residue for the effective inhibition. In this study, we synthesized a series of acylated peptide derivatives focused on the tryptophan residue to develop potent myostatin inhibitors. As a result of the investigation, a more potent derivative of peptide A was successfully identified in which the N-terminal tryptophan residue is replaced with a 2-naphthyloxyacetyl moiety to give an inhibitory peptide three times (1.19+/-0.11 mum) more potent than parent peptide A (3.53+/-0.25 mum). This peptide could prove useful as a new starting point for the development of improved inhibitory peptides.

 

[Michael Scally MD]

[Myostatin] Novartis’ ‘Breakthrough’ Muscle Drug Bimagrumab Flunks A Late-Stage Trial
https://www.morphosys.com/media-investors/media-center/morphosys-ag-morphosys-provides-update-on-results-from-partners-phase

Novartis ($NVS) buried some bad pipeline news in its quarterly report today. The pharma giant says that its “breakthrough” drug bimagrumab (BYM338) failed a Phase IIb/III study for a rare, muscle-wasting disease called sporadic inclusion body myositis--putting a drug that has garnered blockbuster peak sales projections under a cloud.

Novartis kept it short and sour, saying that the drug did not hit the primary endpoint. The company plans to evaluate the full data set before it decides on next steps. But for now, it looks like the latest--and biggest--failure in a string of flops in this niche R&D field.

Novartis jumped on board MorphoSys' antibody discovery platform to find BYM338. The treatment reins in myostatin, and investigators have cited its added potential for cachexia, COPD and sarcopenia.

Novartis’ setback for the lead clinical product in the field could be Scholar Rock’s advantage. The Cambridge, MA-based biotech scored a $36 million B round for its new and perhaps improved myostatin blocker, looking to build muscle in patients suffering from muscle atrophy. http://www.scholarrock.com/programs/SRK-015.html

Knocking down myostatin, though, could also be potentially dangerous. Peter Ganz at UCSF has also studied myostatin in preclinical studies, recently determining that lower levels of that protein alongside reduced levels of GDF11 were linked to thickening heart muscles and heart failure.

It's also no simple matter to knock down myostatin in order to build muscle to fight wasting, as Atara--an Amgen ($AMGN) spinoff--found out when its clinical candidate PINTA 745 failed a Phase II study for protein energy wasting in patients with end-stage renal disease, forcing the biotech to halt development efforts and switch focus to cancer.

Back in 2011, Acceleron ($XLRN) and Shire ($SHPG) also halted clinical work on ACE-031, another myostatin drug with big dreams in fighting muscle wasting, then decided to scrap it altogether in 2013 after running some additional preclinical tests.

 

[Michael Scally MD]

Smad7 Gene Delivery Prevents Muscle Wasting Associated with Cancer Cachexia in Mice

An unfortunate morbidity associated with cancer is muscle wasting, known as cachexia, where healthy cells erode in the face of malignancy.

Cachexia has been difficult to treat, and the most promising new therapies inhibiting ActRIIB ligands, such as myostatin, a protein that promotes muscle breakdown, have been pulled after clinical trials indicated safety issues.

Targeting ActRIIB ligands may still be possible—just in a different way, to avoid toxicity.

Winbanks et al. demonstrated that gene therapy could be used to block ActRIIB ligands’ catabolic signaling.

Delivering the gene Smad7 to mice with tumors prevented muscle atrophy and preserved muscle mass and force production by inhibiting ActRIIB signaling.

The Smad7 gene therapy did not affect other organs, suggesting that safely targeting ActRIIB signaling is possible.

Winbanks CE, Murphy KT, Bernardo BC, et al. Smad7 gene delivery prevents muscle wasting associated with cancer cachexia in mice. Science Translational Medicine 2016;8(348):348ra98-ra98. Smad7 gene delivery prevents muscle wasting associated with cancer cachexia in mice | Science Translational Medicine

Patients with advanced cancer often succumb to complications arising from striated muscle wasting associated with cachexia. Excessive activation of the type IIB activin receptor (ActRIIB) is considered an important mechanism underlying this wasting, where circulating procachectic factors bind ActRIIB and ultimately lead to the phosphorylation of SMAD2/3.

Therapeutics that antagonize the binding of ActRIIB ligands are in clinical development, but concerns exist about achieving efficacy without off-target effects. To protect striated muscle from harmful ActRIIB signaling, and to reduce the risk of off-target effects, we developed an intervention using recombinant adeno-associated viral vectors (rAAV vectors) that increase expression of Smad7 in skeletal and cardiac muscles.

SMAD7 acts as an intracellular negative regulator that prevents SMAD2/3 activation and promotes degradation of ActRIIB complexes. In mouse models of cachexia, rAAV:Smad7 prevented wasting of skeletal muscles and the heart independent of tumor burden and serum levels of procachectic ligands.

Mechanistically, rAAV:Smad7 administration abolished SMAD2/3 signaling downstream of ActRIIB and inhibited expression of the atrophy-related ubiquitin ligases MuRF1 and MAFbx.

These findings identify muscle-directed Smad7 gene delivery as a potential approach for preventing muscle wasting under conditions where excessive ActRIIB signaling occurs, such as cancer cachexia.

 

[Michael Scally MD]

Myostatin Inhibitor ACE-031 Treatment of Ambulatory Boys with Duchenne Muscular Dystrophy

INTRODUCTION: ACE-031 is a fusion protein of activin receptor type IIB and IgG1-Fc, which binds myostatin. It aims to disrupts its inhibitory effect on muscle development and provide potential therapy for myopathies like Duchenne muscular dystrophy (DMD).

METHODS: ACE-031 was administered subcutaneously every 2-4 weeks to DMD boys in a randomized, double-blind, placebo-controlled, ascending dose trial. The primary objective was safety evaluation. Secondary objectives included characterization of pharmacokinetics and pharmacodynamics.

RESULTS: ACE-031 was not associated with serious or severe adverse events. The study was stopped after the second dosing regimen due to potential safety concerns of epistaxis and telangiectasias. A trend for maintenance of the 6 minute walk test (6MWT) distance in ACE-031 groups compared to decline in placebo (not statistically significant) was noted, as was a trend for increased lean body mass, bone mineral density (BMD), and reduced fat mass.

CONCLUSION: ACE-031 demonstrated trends for pharmacodynamic effects on lean mass, fat mass, BMD, and 6MWT. Non-muscle-related adverse events contributed to the decision to discontinue the study. Myostatin inhibition is a promising therapeutic approach for DMD.

Campbell C, McMillan HJ, Mah JK, et al. Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial. Muscle Nerve. Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial - Campbell - 2016 - Muscle & Nerve - Wiley Online Library

 

[master.on]

It looks like Histone Deacetylase Inhibitors HDACs DO inhibit myostatin
Histone Deacetylase Inhibitors in the Treatment of Muscular Dystrophies: Epigenetic Drugs for Genetic Diseases

 

[Dr JIM]

Myostatin Inhibitor ACE-031 Treatment of Ambulatory Boys with Duchenne Muscular Dystrophy

INTRODUCTION: ACE-031 is a fusion protein of activin receptor type IIB and IgG1-Fc, which binds myostatin. It aims to disrupts its inhibitory effect on muscle development and provide potential therapy for myopathies like Duchenne muscular dystrophy (DMD).

METHODS: ACE-031 was administered subcutaneously every 2-4 weeks to DMD boys in a randomized, double-blind, placebo-controlled, ascending dose trial. The primary objective was safety evaluation. Secondary objectives included characterization of pharmacokinetics and pharmacodynamics.

RESULTS: ACE-031 was not associated with serious or severe adverse events. The study was stopped after the second dosing regimen due to potential safety concerns of epistaxis and telangiectasias. A trend for maintenance of the 6 minute walk test (6MWT) distance in ACE-031 groups compared to decline in placebo (not statistically significant) was noted, as was a trend for increased lean body mass, bone mineral density (BMD), and reduced fat mass.

CONCLUSION: ACE-031 demonstrated trends for pharmacodynamic effects on lean mass, fat mass, BMD, and 6MWT. Non-muscle-related adverse events contributed to the decision to discontinue the study. Myostatin inhibition is a promising therapeutic approach for DMD.

Campbell C, McMillan HJ, Mah JK, et al. Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial. Muscle Nerve. Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial - Campbell - 2016 - Muscle & Nerve - Wiley Online Library

As I mentioned previously adverse effects resulted in the discontinuation of this and MANY other MYOSTATIN studies that "showed promise" as SKM anabolic promoters.

Its a known reality in research centers
relatively few "non-beneficial" studies
are ever published and that's unfortunate bc forum readers are left with a plethora of "good" research wo knowing or understanding the bad!

 

[Michael Scally MD]

[OA] The Function of Myostatin In the Regulation of Fat Mass in Mammals

Myostatin (MSTN), also referred to as growth and differentiation factor-8, is a protein secreted in muscle tissues. Researchers believe that its primary function is in negatively regulating muscle because a mutation in its coding region can lead to the famous double muscle trait in cattle.

Muscle and adipose tissue develop from the same mesenchymal stem cells, and researchers have found that MSTN is expressed in fat tissues and plays a key role in adipogenesis. Interestingly, MSTN can exert a dual function, either inhibiting or promoting adipogenesis, according to the situation.

Due to its potential function in controlling body fat mass, MSTN has attracted the interest of researchers.

In this review, we explore its function in regulating adipogenesis in mammals, including preadipocytes, multipotent stem cells and fat mass.

Deng B, Zhang F, Wen J, et al. The function of myostatin in the regulation of fat mass in mammals. Nutr Metab (Lond) 2017;14:29. http://nutritionandmetabolism.biomedcentral.com/articles/10.1186/s12986-017-0179-1

 

[JayWaWa]

Try YK-11 from EA. Ive had good results.