Dystrophin and the Dystrophin Associated Protein Complex

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Myoblast cell differentiation

Myostatin also regulates myoblast differentiation through inhibition of the expression of myogenic transcription factors, such as Pax3, MyoD and Myf5, ((Rios, Carneiro et al. 2002); (Amthor, Huang et al. 2002)). In C2C12 myoblasts, overexpression of myostatin reduces expression of genes encoding muscle structural proteins (MyHC IIb, Troponin I, desmin), and decreases the expression of myogenic transcription factors (MyoD, Myf5 and myogenin) ((Langley, Thomas et al. 2002); (Durieux, Amirouche et al. 2007)). It has been reported that overexpression or addition of myostatin to C2C12 cells induces a decrease in MyoD and myogenin expression via activation of Erk1/2 ((Yang, Chen et al. 2006), (Huang, Chen et al. 2007)). The myogenic factors MyoD and Myf5 induce the activation of the Mstn promoter, which shows the existence of a negative feed-back loop between myogenic factors and myostatin (Salerno, Thomas et al. 2004).

Muscle cell regeneration

Some studies have shown that myostatin controls muscle fiber size by maintaining the satellite cells in a quiescent state and inhibiting protein synthesis (Thomas, Langley et al. 2000). These authors show that myostatin acts on the proliferation and differentiation of myoblasts during muscle growth, but also during regeneration. Recent data on the regeneration of skeletal muscle in Mstn-/- mice show the importance of myostatin in this process. In the absence of myostatin, there is an increase of activation and self-renewal of satellite cells ((McCroskery, Thomas et al. 2003); (Wagner, Liu et al. 2005)), an effect mediated by decreased expression of Pax7 (McFarlane, Hennebry et al. 2008) (Figure 23). However, other studies came to an opposite conclusion and show that there is no difference in the number of satellite cells or myonuclei in the absence of myostatin, and that the hypertrophy is the result of an increase of the cytoplasmic volume (Amthor, Otto et al. 2009). A recent study, suggested that myostatin inhibition induces first the increase of fibers size and then the activation of satellite cells (Wang and McPherron 2012).

Therapeutic strategies based on myostatin blockade

There are several muscle diseases for which a myostatin inhibitor may provide a novel therapeutic approach. Sarcopenia or age related muscle atrophy, affects many elderly people and increases the risk of injury and impairs their quality of life. Increased muscle mass could restore muscle strength and prevent injuries. Cachexia is a form of muscle wasting that affects cancer patients or patients with severe cardiomyopathy. Increased muscle strength in cachectic patients may improve quality of life, improve response to cancer therapy, and increase life span. There are also a variety of muscular dystrophies, including Duchenne muscular dystrophy, for which increased skeletal muscle bulk may provide a therapeutic benefit.
Overexpression of myostatin in adult mice is responsible for the appearance of a cachexia with severe muscle atrophy (Zimmers, Davies et al. 2002). It also contributes to loss of muscle mass in patients affected with the HIV (Gonzalez-Cadavid, Taylor et al. 1998). In ageassociated sarcopenia myostatin mRNA- and protein levels were found to be significantly increased ((Welle 2002), (Leger, Derave et al. 2008)). Such increase of myostatin signaling is accompanied by a decreased activity of pathways involved in muscle hypertrophy such as the IGF1/Akt pathway (Leger, Derave et al. 2008).

The different approaches to induce myostatin blockade

Many different strategies have been employed in order to inhibit either myostatin activity or expression such as (i) the use of antisense-oligonucleotides, (ii) the administration of the myostatin propeptide or (iii) of inhibitory-binding partners like follistatin, (iv) the administration of anti-myostatin blocking antibodies, (v) the use of RNA interference (RNAi) and (vi) the administration of a soluble ActRIIB receptor in order to inhibit the myostatin/ActRIIB pathway.


The soluble activin receptor type IIB (sActRIIB-Fc)

A soluble form of the activin receptor type IIB was produced and used as a therapy to increase muscle mass. To stabilize the protein, the ActRIIB was fused to Fc-fragments, which allow systemic application in different species including human. This soluble receptor can sequester the free myostatin and others ligands and prevent their binding to the endogenous transmembrane receptors ((Lee, Reed et al. 2005); (Morrison, Lachey et al. 2009); (Sako, Grinberg et al. 2010); (Souza, Chen et al. 2008)). Many studies show the potential of sActRIIB-Fc to induce muscle growth and/or to prevent muscle loss in wildtype mice as well as in mouse models for different diseases. Treatment with sActRIIB-Fc improves muscle function in mouse models for DMD, amytrophic lateral sclerosis and myotubular myopathy mouse by increasing muscle weight and strength ((Cadena, Tomkinson et al. 2010); (George Carlson, Bruemmer et al. 2011); (Morrison, Lachey et al. 2009); (Lawlor, Read et al. 2011)). In several animal models of cancer cachexia, blockade of the myostatin/ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior skeletal muscle loss (Zhou, Wang et al. 2010). Regarding the promising potential of this molecule to inhibit the myostatin/ActRIIB pathway and to promote muscle growth and force generation, we decided to use this molecule in our project.

Table of contents :

Table of Contents
1.1 General introduction
1.2 Structure of muscle tissue
1.3 Muscle fibers and properties
1.3.1 Contractile properties
1.3.2 Metabolic properties
1.4 Glucose and lipid metabolism of skeletal muscle
1.4.1 The anaerobic metabolic pathway in muscle
1.4.2 The aerobic metabolic pathway in muscle
1.4.3 The PPAR signaling and metabolism
1.4.4 Targets of the PPARs
1.5 Regulation of muscle mass
1.5.1 Muscle atrophy
1.5.2 Muscle hypertrophy
1.6 Muscle regeneration
1.7 Response of skeletal muscle to repetitive muscle damage
2.1 History and disease description
2.2 The DMD gene
2.3 Mutations of the DMD gene
2.4 Dystrophin and the Dystrophin Associated Protein Complex
2.5 Dystrophin isoforms
2.6 The Dystrophin Associated Protein Complex
2.7 Animal models for DMD
2.7.1 The mdx mouse
2.7.2 The GRMD dog
2.7.3 The HFMD cat
2.8 Revertant fibers
2.9 Treatment strategies for DMD
2.9.1 Gene therapy
2.9.2 The exon skipping
2.9.3 Cell therapies
2.9.4 The pharmacological approach
3.1 Myostatin gene and protein structure
3.2 The myostatin knockout mouse model
3.3 Myostatin expression
3.4 The myostatin signaling pathway
3.5 Regulation of myostatin activity
3.5.1 Molecules binding myostatin
3.6 The function of myostatin
3.6.1 Myoblast cell proliferation
3.6.2 Myoblast cell differentiation
3.6.3 Muscle cell regeneration
3.6.4 The role of myostatin in adipogenesis
3.6.5 Contractile phenotype
3.6.6 Muscle metabolism
3.7 Therapeutic strategies based on myostatin blockade
3.7.1 The different approaches to induce myostatin blockade
3.7.2 Myostatin blockade as a therapy against DMD
1. Part 1: Role of myostatin in the regulation of muscle energetic metabolism in mouse models 
1.1 Effect of the ActRIIB blockade in wildtype and mdx mice
1.2 Effect of the absence of myostatin in the Mstn-/- mouse model
2. Part 2: The role of the myostatin blockade in combination with gene therapy muscular dystrophy.
1. Myostatin and muscle force
2. Myostatin and endurance capacity
3. Myostatin and muscle metabolism
4. Myostatin and mitochondria
5. Myostatin and vascularization
6. Myostatin and heart muscle
7. Myostatin blockade as a therapeutic strategy


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