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“External” signals: the action of inflammatory cells

Satellite cell behavior can be modulated significantly by the presence of growth factors, neighboring cells, and surrounding cellular matrix. It has been shown that evenbrief periods of satellite cell growth in vitro leads to a marked reduction in their myogenic and self-renewal capacities as compared to freshly isolated satellite cells (Montarras, Morgan et al. 2005). Blau and colleagues further demonstrated that a more elastic cell substrate (in contrast to ‘hard’ plastic) increased primary myoblast self-renewal and regenerative capacity when grafted into injured muscle (Gilbert, Havenstrite et al. 2010).
In addition to the physical properties of the satellite cell environment, cytokines and other diffusible molecules produced by surrounding cells are important. Christov and colleagues observed that satellite cells are invariably located near small vessels, and that  endothelial cells promote satellite cell proliferation through IGF-1, FGF, HGF and VEGF secretion (Christov, Chretien et al. 2007). In turn, differentiating myoblasts promote angiogenesis. They proposed that a positive feedback between these two cell types promotes faster and properly patterned tissue repair. Following muscle damage, proinflammatory monocytes accumulate at the site of injury and clear away cellular debris.
This step is followed by a conversion of monocytes into anti-inflammatory macrophages, mediated by the p38-MKP1 balance, that stimulate myogenesis and fiber growth (Fig.7) (Arnold, Henry et al. 2007; Perdiguero, Sousa-Victor et al. 2011). When inflammatory monocytes are depleted at the time of injury, muscle regeneration is completely abrogated due to persistence of necrotic fibers (Arnold, Henry et al. 2007). These experiments demonstrated the crucial role of inflammatory cells in muscle repair and the importance of cellular debris removal. In addition to promote myogenesis, macrophages exert an antiapoptotic effect on myoblasts and newly formed myotubes by direct cell contact through cell adhesion molecules associations such as VCAM-1/VLA-4 or PECAM-1/PECAM-1 (Sonnet, Lafuste et al. 2006). Finally, macrophages induce mesoangioblasts migration to the site of injury through HMGB1, TNFa and MMP9 secretion (Lolmede, Campana et al. 2009). Taken together, these data demonstrate vascular-mediated paracrine effects on the stem cell niche that play a key role in coordinating stem cell responses, leading to the proposal of a transient vascular amplifying/differentiating niche in the regeneration process (Abou-Khalil, Le Grand et al. 2009; Mounier, Chretien et al. 2011).

“Internal” signals: the myogenic/adipogenic balance

In addition to vascular cells, muscle-resident interstitial cells also influence muscle regeneration. First, connective tissue fibroblasts identified by Tcf4 expression proliferate in close proximity to satellite cells following injury (Murphy, Lawson et al. 2011). Conditional ablation of Tcf4+ cells prior to muscle damage leads to smaller regenerated fibers with fewer satellite cells due to premature differentiation, suggesting that fibroblasts normally provide signals that regulate satellite cell expansion during regeneration (Murphy, Lawson et al. 2011). This was further confirmed by in vitro experiments in which myoblasts cultured in the presence of Tcf4+ fibroblasts form larger myotubes containing more nuclei (Mathew, Hansen et al. 2011), and by the observation that C2C12 form more mature myotubes with better survival when cultured on a fibroblast feeder-layer (Cooper, Maxwell et al. 2004). In turn, satellite cells ablation not only leads to a complete loss of muscle  regeneration, as observed by others, but also to a defect in fibroblast recruitment at the onset of regeneration followed by connective tissue expansion (Murphy, Lawson et al. 2011). Taken together, these results demonstrate that satellite cells and fibroblasts reciprocally regulate the expansion of each other to ensure efficient muscle repair. It was further proposed that fibroblasts and atypical myogenic stem cells are recruited to the site of injury by factors secreted by satellite cells (Wang and Rudnicki 2012).
Adipogenic progenitors also participate in muscle homeostasis and regeneration. Recently, two populations with similar characteristics have been identified in the interstitial space of skeletal muscle. Mesenchymal progenitors are characterized by PDGFRa expression (Uezumi, Fukada et al. 2010), and fibro/adipogenic progenitors (FAPs) have been isolated upon Sca1 expression (Joe, Yi et al. 2010). These cells display a strong adipogenic potential in vitro and differentiate into adipocytes in models favoring fat deposition. In addition, FAPs become activated upon injury and promote myoblast differentiation through cell-cell signaling (Joe, Yi et al. 2010) whereas the adipogenic fate of PDGFRa+ cells is strongly inhibited by myotubes (Uezumi, Fukada et al. 2010). It is tempting to speculate that mesenchymal PDGFRa+ cells and FAPs are overlapping populations, nonetheless, these adipogenic progenitors share the property of adopting different fates depending on the surrounding environment as well as promote differentiation of neighboring myogenic progenitors (Joe, Yi et al. 2010). The authors propose that a balance between satellite cell-dependent myogenesis and PDGFRl+ cells/FAPs dependent adipogenesis regulates muscle homeostasis and regeneration (Fig.8). Another recent study demonstrated that the combined injection of fetal CD34+ myogenic, adipogenic, and angiogenic progenitors into damaged muscle leads to improved regeneration capacity compared to the injection of the myogenic fraction alone (Dupas, Rouaud et al. 2011). Taken together, these data provide a clear demonstration of interactions between multiple resident cell populations that promote activation of muscle progenitors.
In conclusion, a more complete picture is emerging in which efficient muscle regeneration requires the coordinated interactions of multiple cell types. Satellite cells, atypical myogenic progenitors and non-myogenic populations provide transient supportive niches that promote muscle repair by producing trophic signals favoring myoblast specification and tissue reconstitution. However, the relationship between these diverse cell types remains to be further clarified.

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Muscle hypertrophy during postnatal growth and physical training

Upon birth all skeletal muscle tissues are formed and the number of myofibers is set, such that postnatal growth occurs by a process of fiber hypertrophy. Some exceptions notably exist in several lower vertebrates, such as fish, that undergo continuous postnatal growth through both hypertrophy and hyperplasia processes (Mommsen 2001; Steinbacher, Haslett et al. 2007). Organ growth occurs when the rate of protein synthesis is higher than the rate of protein degradation. In skeletal muscle, accretion of progenitors is more rapid compared to other tissues and therefore the proportion of muscle proteins relatively to total body proteins is significantly increased (about 45% in rats) (Fig.9) (Davis and Fiorotto 2009). Skeletal muscle postnatal growth is allowed by intense proliferation and differentiation of satellite cells which provide additional nuclei to myofibers (Shafiq,
Gorycki et al. 1968; Moss and Leblond 1971; Schultz 1996; Davis and Fiorotto 2009). The dependence of neonatal muscle hypertrophy on satellite cells has been demonstrated by the study of Pax7-null mice, which possess a normal pool of satellite cells at birth but their number rapidly declines leading to severely impaired muscle growth and survival (Seale, Sabourin et al. 2000; Oustanina, Hause et al. 2004).
Postnatal myofiber hypertrophy occurs in 2 phases. In the first phase, between birth and 3 weeks old, the number of myonuclei per fiber rapidly increases by fusion of satellite cells and the myofiber volume is multiplied by 5 (White, Bierinx et al. 2010). About 80% of satellite cells in neonatal muscle are proliferating (Schultz 1996; White, Bierinx et al. 2010), mostly under the activation of IGF-1 (Adams 1998; Shavlakadze, Chai et al. 2010). IGF-1 enhancing effect on muscle growth has been demonstrated in mice over-expressing IGF-1, which display enhanced postnatal muscle growth and protein accretion leading to significantly bigger muscles (Fiorotto, Schwartz et al. 2003). Before 9 days old, the number of satellite cells per fiber is similar to the rate of myonuclear addition per day (~13 cells) (White, Bierinx et al. 2010). Since the satellite cell number was found to be relatively stable over this period, the authors propose that most satellite cells are undergoing asymmetric divisions, each giving rise to both one myonucleus and one new satellite cell, as first suggested by Moss and Leblond in 1971 (Moss and Leblond 1971). Between 2 and 3 weeks old, the available number of satellite cells decreases until the adult configuration is established. As such, by 3 weeks of age, the adult number of myonuclei and satellite cells is already established in the mouse muscle. In the second phase of postnatal myofiber hypertrophy, from 3 weeks old to adulthood, the myofiber volume is multiplied by 3 through expansion of the myonuclear domain without addition of new myonuclei (Mantilla, Sill et al. 2008; White, Bierinx et al. 2010). Down-regulation of IGF-1 and HGF (Alexandrides, Moses et al. 1989; Jennische, Ekberg et al. 1993) concomitant with the up-regulation of inhibitors such as myostatin (Suryawan, Frank et al. 2006) induce satellite cells to exit the cell cycle and enter quiescence.

Table of contents :

1. Generalities about skeletal muscle
1.1. Skeletal muscle structure and function
1.2. Embryonic development of vertebrate limb skeletal muscles
2. Postnatal skeletal muscle stem cells
2.1. The satellite cell
2.2. Non-satellite muscle progenitors
3. Influence of the niche on stem cell behavior
3.1. “External” signals: the action of inflammatory cells
3.2. “Internal” signals: the myogenic/adipogenic balance
1. Changes in muscle mass throughout life
1.1. Muscle hypertrophy during postnatal growth and physical training
1.2. Age and disease-related loss of muscle mass
2. The major signaling pathways regulating muscle size
2.1. Myostatin, a potent inhibitor of muscle mass
2.2. Myostatin non-canonical pathways
2.3. A myostatin endogenous antagonist: follistatin
3. Pharmaceutical approaches to induce skeletal muscle hypertrophy
3.1. Targeting muscle mass via myostatin inhibition
3.2. Satellite cells and muscle hypertrophy
RATIONALE. Introduction at a glance and objectives of the thesis
1. PICs: multipotent progenitors or mixed population?
1.1. Adult PICs versus juvenile PICs
1.2. Adult PICs versus other stem cells of the skeletal muscle niche
2. PICs as a therapeutic target
2.1. PICs are a source of positive signals for muscle growth
2.2. PICs constitute an easily recruitable population


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