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Myostatin
More recently, myostatins have achieved some notoriety. Myostatin is a member of transforming growth factor β family, which is heavily conserved. It was first described in 1997 by McPherron and colleagues,10 although it may have been previously described in 1987 in Duchenne muscular dystrophy.11 Natural and activating mutations of the myostatin gene in cattle are associated in Belgian Blue cattle in double-muscling of these heavily muscled cattle.12–14 Glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of the myostatin gene expression and is blocked by the steroid blocker RU-486. Dexamethasone treatment continued for 10 days, however, results in normal intramuscular concentration of myostatin. At least one mechanism of the ubiquitin proteolytic system is an NF-κB–independent and FOXO1-dependent mechanism activated by increased ubiquitin-associated genes, atrogin-1, MuRF1, and E214k.15
The significance is that inactivation of myostatin leads to muscle growth; the injection of RNA antisense nucleotides increased muscle growth in both normal and cancer cachectic mice.16 Myostatin circulates in adult mice as a propeptide, which maintains it with a C-terminal dimer in a latent inactive state. Acidosis cleaves the shielding protein, as do metalloproteinases (which are implicated in cancer). Furthermore, injection of a mutant propeptide resistant to cleavage by BMP-1/TLD causes a significant increase in muscle mass when injected into adult mice. Although myostatin has been implicated in cachexia associated with AIDS and associated with liver cirrhosis, preliminary investigations in sepsis have failed to reveal increases in myostatins. Finally, oral glutamine in rats partially prevents muscle atrophy induced by dexamethasone; myostatin expression is also inhibited.
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URL: https://www.sciencedirect.com/science/article/pii/S0039610911000090
Myostatin is an inhibitor of muscle regeneration. It has a direct effect inhibiting satellite cell production. A double deletion of the myostatin gene leads to muscle hypertrophy in mice, cows, and in a single human [44]. Amgen has developed “peptobodies” to myostatin, which in animal studies appear to cause muscle hypertrophy.
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URL: https://www.sciencedirect.com/science/article/pii/S0025712506000575
Myostatin
Myostatin is an inhibitor of muscle growth; tissues may need to be inhibited as well as stimulated (eg, at the conclusion of the healing process). Myostatin possibly acts by turning down sarcolemmal satellite cell function. A mutant, less active (ie, less inhibiting) myostatin is responsible for the highly exaggerated physique in Belgian Blue and Blonde d'Aquitaine beef cattle breeds.27 In the racing whippet, a mutation in the MSTN gene involving the deletion of only two base pairs results in premature termination of mRNA, which translates a truncated, and less effective, form of myostatin, giving greater muscle mass and faster running speed in the heterozygous condition.28 But whippets homozygous for the gene carry too much muscle and are actually slower.28,29 In the mouse mdx-model of muscular dystrophy, blockading the activity of the normal inhibitory myostatin, by means of a specific monoclonal antibody, has also been shown to increase muscle size and force and power, again possibly by disinhibiting satellite cells. Experiments on mice, genetically engineered as Schwarzenegger mice to produce less effective myostatin, have shown that diminishing this antigrowth factor induces hypertrophy and, unusually, muscle hyperplasia, again possibly through stimulating satellite cell function. Just as in the cases of the two excessively muscled cattle breeds and the whippet, so there are possible human mutations with regard to myostatin and its receptor. A 3-year-old Michigan boy gained wide media publicity in 2009 due to, among other things, a variety of simple strength tests (including sit up, pull up, and grip measures), which indicated that he was equivalent to the upper percentiles of 6-year-olds in some tests and the lower percentiles of 7-year-olds in one test. His grip strength was 300% greater than that of a peer group of larger children. Nevertheless, he had fairly normal myostatin levels and the assumption is that a mutation may lie in his myostatin receptors being less effective (the opposite of the more effective natural erythropoietin (EPO) receptor mutation of the Maentyranta family [discussed later]). An equivalent hyperstrength case was described in another young boy, but it was due to a defective gene for mysostatin rather than a receptor error.30 Some bodybuilders obtain myostatin inhibitors over the Internet, but that is simple doping, not gene doping. In a different context, the syrinx vocal organ of the ringdove contains superfast muscles31 and one wonders if its code and accessories might be adapted for use in some future human sprinters?
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URL: https://www.sciencedirect.com/science/article/pii/S0889852909000930
Myostatin
Myostatin, as briefly stated, is a protein secreted by muscle cells that inhibits muscle synthesis and differentiation and promotes muscle degradation.24,85 It is primarily activated by elevated ammonia levels precipitated by cirrhosis, though other stimuli include decreased testosterone and increased TNF-α.24 Specifically, ammonia activates nuclear factor κβ, which, in turn, stimulates the production of myostatin.86 Myostatin exerts its action through multiple modalities: (1) it inhibits the Akt and mTOR pathways involved in muscle growth and differentiation and; (2) it induces the proteosome–ubiquitin complex (and muscle breakdown) through the activation of effectors of the proteosome such as atrogin-1 and muscle RING-finger-1 (Figure 2).24,83
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URL: https://www.sciencedirect.com/science/article/pii/S0973688322001542
2.5 Myostatin
Myostatin, a member of the transforming growth factor beta superfamily, is an extracellular cytokine dominantly expressed in skeletal muscles which is known to play the important role in the negative regulation of muscle mass [53,54]. Myostatin appears to be a key player in the integrated physiology of muscle, fat, and bone [55]. It is unclear whether myostatin directly affects fat and bone, or indirectly via muscle. Myostatin has high affinity to the activin IIB receptor and it has been shown that administration of soluble activin IIB receptor resulted in an improvement in body and muscle weights in mice [56]. However, myostatin and the MAFbx expression remained unaffected by both the HF and age [57].
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URL: https://www.sciencedirect.com/science/article/pii/S0167527315306781
Myostatin
Myostatin is a member of the transforming growth factor-β (TGF-β) family, which is expressed in skeletal muscle, and inhibits muscle growth.89 Myostatin downregulates the Akt/mammalian target of rapamycin (Akt/mTOR) pathway. Myostatin decreases protein synthesis and muscle cell synthesis.90 Myostatin represents an important potential therapeutic approach for sarcopenia and other muscular disorders, such as muscular dystrophy.
In animals and humans, mutations in the myostatin gene result in increased muscle mass.91,92 A single gene administration of myostatin inhibitor enhances muscle mass and strength in mouse.93 Antagonism of myostatin enhanced muscle tissue regeneration in aged mice.92 The increase in muscle mass is caused by both hypertrophy and hyperplasia.94
Different approaches to inhibit the effect of myostatin are currently in development.95 Hormones such as follistatin, a myostatin-binding protein, and drugs such as trichostatin A can antagonize myostatin and are potential new therapeutic for patients with sarcopenia.96–99 The effects of follistatin, originally named follicle-stimulating hormone (FSH)–suppressing protein, are multiple. It induces muscle hypertrophy through satellite cell proliferation by inhibiting both myostatin and activin.100
Activin is another TGF-β expressed by the muscle. At the 5th Cachexia Conference held in December 2009 in Barcelona, Spain, Kate Murphy from the University of Melbourne, Australia, presented on the effects of myostatin antibody on skeletal muscle in aged mice.41 The authors reported a statistically significant increased muscle mass by 8% to 18%, muscle fiber size by 12%, and muscle strength by 35% after 14 weeks of treatment. At the same time, percentage of type IIa fibers increased by 114% and muscle fiber oxidative capacity improved by 39%.41 Recombinant human antibodies to myostatin are currently being tested in humans with muscular dystrophy.
The other approach is to use a soluble myostatin decoy receptor (activin type IIB receptor; ActRIIB-Fc) or an extracellular domain of the human ActRIIB receptor. In the Barcelona meeting, Peter Bialek from Pfizer in Cambridge, Massachusetts, reported on cachexia models of mice, showing promising results of ActRIIB-Fc on muscle mass and function.41 In a randomized, double-blind, phase I study in healthy postmenopausal women, Jasbir Seehra from Acceleron Pharma in Cambridge, Massachusetts, reported a 2.4% to 2.6% increase in lean body mass after only 15 days of treatment. The treatment was safe and well tolerated.41 In the future, gene administration of myostatin inhibitor proteins may also be a option to enhance muscle mass and strength.93 However, experts have reported that muscle tissue may be more susceptible to muscle and tendon injuries in mice with myostatin deficiency.101
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URL: https://www.sciencedirect.com/science/article/pii/S0749069011000218
Myostatin (muscle-to-bone interaction)
Myostatin, a cytokine that belongs to the TGF-β family, suppresses skeletal muscle regeneration and hypertrophy. It is produced, secreted, and acts in skeletal muscles [22]. Myostatin is a major regulator of proliferation and differentiation of mesenchymal stem cells such as satellite cells. Myostatin secretion suppresses the differentiation of satellite cells, causing a decrease in its self-renewal ability [23]. It has also been shown that myostatin-null mice have reduced body fat and increased bone mineral density, bone marrow-derived stem cells, bone formation, differentiation, and repair, and muscle strength. It was also found that myostatin inhibitors, which affect the inhibition of myostatin receptor (ActRIIB) in osteoblasts, lead to increased bone formation in mice. Myostatin directly affects the proliferation and differentiation of osteoprogenitor cells, suggesting that myostatin suppression is likely to enhance both muscle mass and bone strength [24].
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URL: https://www.sciencedirect.com/science/article/pii/B9780128200889000214
Myostatin
Myostatin, a myokine that belongs to TGF-β superfamily proteins, is a potent suppressor of skeletal muscle mass and development. After binding the activin receptor type IIB (ACVR2B), myostatin activates the phosphorylation of Smad2 and Smad3. Deletion of myostatin in mice leads to skeletal muscle hypertrophy (McPherron et al., 1997), whereas its overexpression causes decrease in muscle mass (Zimmers et al., 2002). Moreover, myostatin knock out mice exhibit improved bone strength following physical activity (Hamrick et al., 2006). While myostatin inhibits osteoblastic differentiation of bone marrow mesenchymal cells (Hamrick et al., 2007), it enhances osteoclast formation through Smad2-dependent activation of the nuclear factor of activated T cells (NFATc1) and increases osteoclastic marker genes, such as integrin αVβ3, DC-STAMP and calcitonin receptor (Dankbar et al., 2015). Moreover, treatment with ACVR2B-Fc, a soluble myostatin decoy receptor that blocks the myostatin binding, prevents muscle loss in a mouse model of osteogenesis imperfecta (Jeong et al., 2014). The effectiveness of ACVR2B-Fc has been observed also in postmenopausal women, in which it increased biomarkers of bone formation, while decreasing those of bone resorption (Ruckle et al., 2009). However, ACVR2B-Fc might cause several side effects since ACVR2B binds several growth and development hormones other than myostatin and is involved in numerous actions in different tissues.
Recent studies have shown that myostatin stimulates the expression of negative regulators of bone formation, such as sclerostin, DKK1, and RANKL in an osteocyte cell line (Ocy454), through the suppression of osteocyte-derived exosomal miR-218, suggesting a novel mechanism in muscle-bone communication (Qin et al., 2017).
Interestingly, Irisin and myostatin are both produced by skeletal muscle and their secretion is inversely regulated by physical activity (MacKenzie et al., 2013). Irisin and its precursor were highly expressed in skeletal muscle of myostatin knock-out mice (Shan et al., 2013), suggesting that skeletal muscle hypertrophy observed in these mice could be also dependent on increased irisin synthesis.
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URL: https://www.sciencedirect.com/science/article/pii/B9780128012383112188
Myostatin is a TGFβ family member that is an inhibitor of skeletal muscle growth [52]. Because the myostatin null mouse (Mstn−/−) has an increased muscle mass due to hyperplasia and hypertrophy, it was bred to the mdx mouse model to determine its effect on muscular dystrophy [53]. The resultant mice had a reduced severity of disease as measured by muscle weight, grip strength, muscle fiber diameter, histology and hydroxyproline content. These findings have translated closer to therapy in that myostatin inhibitors also attenuate the mdx phenotype [54,55]. Although these results have been encouraging and lead to human clinical trials, a second dihybrid cross was undertaken which cautions against the positive results of the mdx/Mstn−/− data. The same myostatin null mutation was bred onto the laminin-deficient mice, dyW/dyW, a model for merosin deficient CMD. In this cross, increased muscle regeneration and muscle mass, due primarily to hyperplasia, were present. However, no improvement of muscle pathology and an increase in pre-weaning mortality was described [56]. The difference between the two models may relate to intrinsic pathologic defects between the two forms of muscular dystrophy. The more severe phenotype of the dyW/dyW mice and/or the lack of tolerance for decreased brown fat in the dyW/dyW mice may also contribute. An alternative strategy that would directly test the contribution of brown fat would utilize the cre-lox technology to eliminate myostatin shortly after birth, beyond the window where brown fat may be required [57]. Over-expression of a dominant negative myostatin exclusively in differentiated muscles may also reflect what can be achieved through pharmacologic inhibition [58].
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URL: https://www.sciencedirect.com/science/article/pii/S0925443906001219
Myostatin, a secreted protein that belongs to the TGF-β family, inhibits muscle growth and regeneration. Skeletal muscle is the main source of myostatin [95]. Treatment of human myoblasts with myostatin reduces Akt, p70S6 kinase, and FoxO1 phosphorylation, and these can be restored by treatment with IGF-I [57]. Skeletal muscle from myostatin knockout mice shows increased Akt protein expression [95]. Interestingly, muscle hypertrophy induced by myostatin inhibition can occur in the absence of Sdc4 or Pax7, both of which are important for SCs activity [96]. It suggested that myostatin inhibition may have beneficial effects in clinical settings in which satellite cells are reduced, such as in sarcopenia. However, myostatin blockade is known to lead to a great increase in muscle mass without increasing muscle force due to mitochondrial depletion [97].
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URL: https://www.sciencedirect.com/science/article/pii/S1043276013000519