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3 Myostatin
Myostatin is a member of the transforming growth factor beta superfamily and is a negative regulator of skeletal muscle mass (McPherron et al., 1997; Whittemore et al., 2003; Bradley et al., 2008; Katsuno et al., 2011). Myostatin is synthesised primarily by skeletal muscle and circulates in the blood as an inactive complex made up of its own propeptide and other inhibitors and appears to act at the level of the muscle satellite cell. It binds with high affinity to the ser/thr kinase ActRIIB receptor on skeletal muscle and tranduces a signal that induces translocation of a Smad complex to the nucleus with consequent activation of a variety of genes including myogenic regulatory factors. A second low affinity interaction involved in receptor activation involves the ALK-4 and ALK-5 kinases (shown schematically in Fig. 1). Myostatin activity appears to be conserved across all species studied from human to dogs, sheep, cattle, rodents and fish. Neutralization of myostatin activity leads to a large increase in muscle mass via hypertrophy that is often two to three times greater than normal muscle mass. Myostatin also modulates muscle regeneration after injury and the lack of myostatin in null mice accelerates regeneration (McCroskery et al., 2005). Thus, neutralization of myostatin may be a novel approach to treat a variety of muscle wasting diseases like ALS. Additional indications for such a therapy include disuse atrophy, cancer cachexia, sarcopenia and muscular dystrophies.
Fig. 1. Myostatin binds to the ser/thr kinase ActRIIB receptor on skeletal muscle and tranduces a signal through the Alk4/5 coreceptor leading to the translocation of a Smad complex to the nucleus with consequent activation of a variety of genes including myogenic regulatory factors.
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URL: https://www.sciencedirect.com/science/article/pii/S0197018612002367
10 Myostatin
Myostatin is a TGF-β family member associated with muscle atrophy due to a variety of conditions in both humans and rodents [156–160]. Myostatin is a negative regulator of skeletal muscle size, as overexpression of myostatin is sufficient to cause muscle wasting [161]. Much of the effect of myostatin on muscle size is related to its known effects on both muscle protein synthesis and protein degradation [162]. However, in addition to altering the balance of protein synthesis and protein degradation, myostatin has also been shown to impair muscle regeneration. Specifically, myostatin prevents satellite cells from expressing MyoD [163]. As discussed above, without the expression of MyoD, muscle regeneration is compromised due to an inability of satellite cells to commit to a myogenic fate and differentiate into damaged muscle.
Myostatin is a soluble cytokine which functions through activation of the ActRIIB receptor [162]. Multiple pharmacological strategies have been tried to decrease myostatin signaling, including the use of soluble ActRIIB receptors and myostatin antibodies [125,164–166]. Specifically in cancer cachexia, a multitude of studies demonstrate that inhibition of myostatin is sufficient to prevent muscle wasting [125,164–167]. In addition to a rescue of muscle mass, Zhou et al. demonstrated that inhibiting myostatin signaling correlated with an increase in the number of BrdU+, Pax7+ cells in tumor-bearing mice [125]. This suggests the possibility that myostatin acts in a similar manner to NF-κB by upregulating Pax7 to impair the regenerative process. Work from our own laboratory and others has been unable to find evidence of myostatin acting upstream of NF-κB, but some evidence does suggest that NF-κB can induce expression of myostatin family members [124,168–170]. Further work will be required to determine the relationship between NF-κB and myostatin and if the impact of myostatin on muscle regeneration is a major contributing factor in cancer cachexia.
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URL: https://www.sciencedirect.com/science/article/pii/S108495211500169X
Abstract
Myostatin is a member of the transforming growth factor (TGF)-β superfamily. It is expressed by animal and human skeletal muscle cells where it limits muscle growth and promotes protein breakdown. Its effects are influenced by complex mechanisms including transcriptional and epigenetic regulation and modulation by extracellular binding proteins.
Due to its actions in promoting muscle atrophy and cachexia, myostatin has been investigated as a promising therapeutic target to counteract muscle mass loss in experimental models and patients affected by different muscle-wasting conditions. Moreover, growing evidence indicates that myostatin, beyond to regulate skeletal muscle growth, may have a role in many physiologic and pathologic processes, such as obesity, insulin resistance, cardiovascular and chronic kidney disease. In this chapter, we review myostatin biology, including intracellular and extracellular regulatory pathways, and the role of myostatin in modulating physiologic processes, such as muscle growth and aging. Moreover, we discuss the most relevant experimental and clinical evidence supporting the extra-muscle effects of myostatin. Finally, we consider the main strategies developed and tested to inhibit myostatin in clinical trials and discuss the limits and future perspectives of the research on myostatin.
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URL: https://www.sciencedirect.com/science/article/pii/S0065242321000809
Myostatin is a key negative regulator of the skeletal muscle growth (Grobet et al., 1997; McPherron and Lee, 1997). Myostatin gene inactivation and knockout studies have shown that mutated myostatin protein or reduced myostatin expression are coupled to marked increases in skeletal muscle mass (Grobet et al., 1997; McPherron and Lee, 1997). It is believed that myostatin signaling participates in the regulation of age-associated muscle atrophy as both serum myostatin and muscle myostatin expression are increased with age (Kawada et al., 2001; Yarasheski et al., 2002). These age-associated increases in myostatin are in turn associated with decreases in fat-free mass and diminished muscle mass (Kawada et al., 2001; Yarasheski et al., 2002). The expression of myostatin can be mechanically regulated with increased loading resulting in decreased myostatin expression (Kawada et al., 2001). Interestingly, it has been reported that inhibition of myostatin by PF-354 enhances aerobic performance in aged mice (LeBrasseur et al., 2009). This increase in muscle endurance was associated with decreased phosphorylation/activation of myostatin downstream molecule Smad3 (LeBrasseur et al., 2009) and impaired Smad4 translocation to the nucleus (Joulia-Ekaza and Cabello, 2007). Therefore, manipulation of myostatin signaling may be a useful strategy to ameliorate the aging-related defects in muscle mechanotransduction and muscle growth.
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URL: https://www.sciencedirect.com/science/article/pii/S1568163709000786
Myostatin
Myostatin is a hormone secreted from muscle, or a myokine. As implied by its name, it inhibits increases in muscle mass. There are several animal models of myostatin deficiency, including mice, dogs and cattle. One person with a mutation in myostatin has been found—he has a significant increase in muscle mass (Schuelke et al., 2004). His bone density has not been reported. Muscle mass and bone density are both significantly increased in the myostatin mutant mouse (Hamrick et al., 2006). Myostatin deficiency in this setting results in exercise-induced gains in bone mass and importantly, resistance to fracture (Hamrick et al., 2006).
Myostatin expression is decreased in human muscle from 1 h after exercise with a persisting substantial decrease at 24 h (Louis et al., 2007). The nadir in expression was 8 h after exercise. In that study the protocol was for 45 min of bike-riding. In another study of insulin resistant men, aerobic exercise at ~ 50% of VO2 max for 6 months maintained a 21% decrease in circulating myostatin (Hittel et al., 2010). Exercise at 50% or 80% of maximum lifting weight also significantly decreased myostatin, with a persisting decrease at 48 h (Schwarz et al., 2016). In contrast, in older women, elastic band exercises did not alter myostatin although the exercise was enough to improve physical performance (Hofmann et al., 2016). The “threshold” dose of exercise for duration or intensity of exercise is not known for myostatin, but half an hour at moderate intensity appears sufficient from the above studies.
Antibody inhibitors of myostatin in people have not produced consistent clinical results. One study in Duchenne׳s patients, where only two doses were received due to epistaxis and telangiectasias showed trends to improved muscle function (Campbell et al., 2017). In androgen-deprived men, 28 days of myostatin inhibitor ACE-031 caused a small but significant increase in lean mass (2.2%) (Padhi et al., 2014). The trials of inhibitors have mostly been of short duration, and or small in size, and there are no reports in people regarding whether there are or are not bone effects.
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URL: https://www.sciencedirect.com/science/article/pii/B978012801238365835X
Abstract
Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily, is a critical autocrine/paracrine inhibitor of skeletal muscle growth. Since the first observed double-muscling phenotype was reported in myostatin-null animals, a functional role of myostatin has been demonstrated in the control of skeletal muscle development. However, beyond the confines of its traditional role in muscle growth inhibition, myostatin has recently been shown to play an important role in metabolism. During the past several years, it has been well established that Smads are canonical mediators of signals for myostatin from the receptors to the nucleus. However, growing evidence supports the notion that Non-Smad signal pathways also participate in myostatin signaling. Myostatin expression is increased in muscle atrophy and metabolic disorders, suggesting that changes in endogenous expression of myostatin may provide therapeutic benefit for these diseases. MicroRNAs (miRNAs) are a class of non-coding RNAs that negatively regulate gene expression and recent evidence has accumulated supporting a role for miRNAs in the regulation of myostatin expression. This review highlights some of these areas in myostatin research: a novel role in metabolism, signal pathways, and miRNA-mediated expression regulation.
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URL: https://www.sciencedirect.com/science/article/pii/S0898656811001409
1 Introduction
Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily, is a critical autocrine/paracrine inhibitor of skeletal muscle growth [1]. The deletion of myostatin in mice induces a dramatic and widespread increase in skeletal muscle mass due to both muscle hypertrophy and hyperplasia [1–3]. The double-muscling phenotype of some cattle and sheep breeds is caused by mutations in their myostatin genes [4–6]. Therefore, the most important myostatin function is the regulation of skeletal muscle growth. However, the biological function of myostatin is not only restricted to muscle growth inhibition but also might have other redundant functions.
Myostatin appears to trigger signaling by directly binding to its serine/threonine kinase receptor [7–9]. Downstream of the receptors, Smads are first demonstrated to be mediators of signals for myostatin [7,8,10]. Beyond the canonical Smad-mediated signal pathway, Non-Smad signal pathways have recently been reported to participate in myostatin signaling [11–14].
Myostatin expression is increased in glucocorticoid-induced muscle atrophy [15,16] as well as skeletal muscle degeneration-related diseases, such as HIV infection [17] and chronic illnesses [18]. The increased myostatin expression is also associated with metabolic disorders, such as obesity [19,20] and diabetes [21]. These results suggest that changes in endogenous expression of myostatin may provide therapeutic benefit for these diseases. MicroRNAs (miRNAs) are a class of non-coding RNAs that negatively regulate gene expression [22] and growing evidence has accumulated supporting a role for miRNAs in the regulation of myostatin expression [23–26].
In this article, we will briefly review the structure and proteclytic processing of myostatin and discuss recent advances in our understanding of its role in metabolism, signal pathways, effects in vitro, microRNA-mediated expression regulation, and potential therapeutic approaches to blocking myostatin activity.
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URL: https://www.sciencedirect.com/science/article/pii/S0898656811001409
Myostatin (GDF-8) is a muscle specific negative regulator of muscle growth (McPherson, Lawler, & Lee, 1997) and a member of the transforming growth factor B family, and, as described in text above, causes double muscling in cattle and mice. In 2004, Schuelke and colleagues described a child who was born, after a normal pregnancy, with both increased muscle mass and increased strength. This individual showed a quadriceps cross-sectional area 7.2 SD above the mean for age and sex matched controls and the ability to hold two 3 kg dumbbells in “horizontal suspension with arms extended” age the age of 4.3 years. The child showed a splice site mutation in the myostatin gene (at IVS1 + 5), and this mutation prevented the production of the myostatin protein. As suggested by McNally (2004), other less dramatic changes in the myostatin gene (or heterozygosity for the splice site mutation) may confer enhanced atheletic prowess in a less conspicuous manner. However, the child's mutation has not been found in any other individuals, and is therefore not a polymorphism driving normal human variation. Furthermore, genetic association studies with myostatin polymorphisms have consistently failed to demonstrate any statistically significant relationship with any human muscle trait (Ferrell et al., 1999; Ivey et al., 2000; Thomis et al., 2004).
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URL: https://www.sciencedirect.com/science/article/pii/S1357272505001536
Myostatin (also known as GDF8), a TGFβ family member structurally related to activins, is specifically expressed in the skeletal muscle lineage and it is as a major negative regulator of muscle growth. Myostatin signals through activin type II receptors and its activities are regulated by the extracellular protein follistatin [11]. Accumulating evidence also implicates myostatin in muscle repair and fibrosis. Work from other groups has shown that myostatin-deficient mice develop significantly less fibrosis and display better muscle regeneration than wild type mice after injury [44]. In agreement with this, mdx mice lacking myostatin are stronger and more muscular than their mdx counterparts and show less fibrosis in the diaphragm, suggesting improved muscle regeneration [56]. Immunological neutralization of myostatin was also shown to attenuate dystrophy by improving muscle regeneration and reducing ECM accumulation in mdx muscle [57]. Conversely, injection of recombinant myostatin protein in vivo stimulates myofibers to express TGFβ. Likewise, it stimulates TGFβ secretion in C2C12 myoblasts in vitro. TGFβ also induces myostatin production, thus suggesting a collaborative action of both pro-fibrotic cytokines on muscle cells. Of note, the physiological role of myostatin in cardiac muscle appears significantly different than in skeletal muscle as it does not induce cardiac hypertrophy and does not modulate cardiac fibrosis in mdx mice [58].
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URL: https://www.sciencedirect.com/science/article/pii/S0014482710002995
Highlights
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Myostatin is a negative regulator of skeletal muscle mass. •
Myostatin increases insulin resistance. •
Myostatin is a major contributor to cardiac cachexia. •
Myostatin inhibition represents a promising therapeutic approach to cachexia in general.
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URL: https://www.sciencedirect.com/science/article/pii/S0009898114001296