Skeletal muscle stem cells

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In this review we shall discuss recent publications on the heterogeneity of muscle stem cells, signaling pathways that affect their behaviour and regulatory mechanisms that underlie their myogenic fate, with reference to insights provided by work on skeletal muscle formation in the embryo as well as the adult, with the mouse as a model of reference.

Introduction

The notion that satellite cells represent the major cell type responsible for post-natal skeletal muscle growth and regeneration has recently received further support [1, 2, 3]. These quiescent cells, located under the basal lamina of muscle fibres, become activated upon injury, proliferate and differentiate into new muscle fibres. During regeneration, the satellite cell pool is also reconstituted. Thus, satellite cells display two hallmarks of stem cells: lineage-specific differentiation and self-renewal.

Section snippets

Heterogeneity between muscle progenitor cells

Skeletal muscle formation [4] (Figure 1) depends on the myogenic regulatory factors, of which MyoD and Myf5/Mrf4 determine muscle cell fate, whereas Myogenin, as well as MyoD and Mrf4, controls differentiation. At the onset of myogenesis in the embryo, Myf5/Mrf4 and then MyoD are directly activated in the dorsal somite by signals from adjacent tissues. Although the initial activation of MyoD depends on Myf5/Mrf4, it is subsequently expressed in the absence of these factors. Selective ablation

Stem cell behaviour in the satellite cell population

The implication of the observed Myf5/Pax7 heterogeneity is that most satellite cells at some stage of muscle development had engaged the myogenic programme and then reverted to a quiescent satellite cell state. Indeed, even in cell culture, activated satellite cells can revert to a Pax7+/MyoD state [19, 20]. The question is whether such cells have less capacity for self-renewal. In the Myf5Cre/Rosa26-YFP experiment, Pax7+/YFP (Myf5) cells were more efficient in reconstituting the satellite

Cell fate decisions and signaling pathways

Numb/Notch antagonism is thought to be involved in stem cell behaviour in many systems [25]. Delta1 stimulated Notch signaling has been implicated in satellite cell mobilisation in adult muscles, and forced activation of this pathway leads to increased regeneration in muscles of ageing mice [26]. Delta1 appears to be produced not only by activated satellite cells but also by injured fibres. This is further illustrated by the muscle regeneration defects displayed by Stra13-deficient mice [27].

Myogenic regulatory mechanisms

Artificially high levels of Pax7 in satellite cells are not compatible with differentiation and Myogenin appears to be crucial for Pax7 downregulation [50]. Rapid Pax protein degradation, essential for myogenic progression, depends on post-transcriptional mechanisms that differ for Pax3 and Pax7 [51]. Interestingly Pax3, but not Pax7, is regulated by ubiquitination dependent proteosomal degradation, involving a novel role for protein monoubiquitination.

Pax3 and Pax7 play an important role in

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

MB and DM thank Didier Rocancourt for the illustrations. Work on myogenesis in the Buckingham laboratory is supported by the Pasteur Institute and the Centre National de la Recherche Scientifique, with grants from the Association Française contre les Myopathies, the EU Integrated Project ‘EuroSyStem’ and EU Networks of Excellence, ‘Cells into Organs’ and ‘MYORES’.

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