Cold Spring Harb Perspect Biol-2012-Bentzinger

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  • 2012; doi: 10.1101/cshperspect.a008342Cold Spring Harb Perspect Biol C. Florian Bentzinger, Yu Xin Wang and Michael A. Rudnicki Building Muscle: Molecular Regulation of Myogenesis

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    Panagiota A. Sotiropoulou and Cedric Blanpain For additional articles in this collection, see

    Copyright 2012 Cold Spring Harbor Laboratory Press; all rights reserved

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  • For additional articles in this collection, see

    Copyright 2012 Cold Spring Harbor Laboratory Press; all rights reserved

    on April 14, 2014 - Published by Cold Spring Harbor Laboratory Press from on April 14, 2014 - Published by Cold Spring Harbor Laboratory Press from

  • Building Muscle: Molecular Regulationof Myogenesis

    C. Florian Bentzinger1, Yu Xin Wang1, and Michael A. Rudnicki1,2

    1The Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Health Research Institute,Ottawa, Ontario K1H 8L6, Canada

    2Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa,Ontario K1H 8M5, Canada



    The genesis of skeletal muscle during embryonic development and postnatal life serves as aparadigm for stem and progenitor cell maintenance, lineage specification, and terminal differ-entiation. An elaborate interplay of extrinsic and intrinsic regulatory mechanisms controlsmyogenesis at all stages of development. Many aspects of adult myogenesis resemble or reit-erate embryonic morphogenetic episodes, and related signaling mechanisms control thegenetic networks that determine cell fate during these processes. An integrative view of all as-pects of myogenesis is imperative for a comprehensive understanding of muscle formation.This article provides a holistic overview of the different stages and modes of myogenesiswith an emphasis on the underlying signals, molecular switches, and genetic networks.


    1 Introduction

    2 Morphogen Gradients and Myogenesis

    3 Genetic Networks Controlling Myogenesis

    4 Adult Myogenesis

    5 Concluding Remarks


    Editors: Patrick P.L. Tam, W. James Nelson, and Janet Rossant

    Additional Perspectives on Mammalian Development available at

    Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a008342

    Cite this article as Cold Spring Harb Perspect Biol 2012;4:a008342


    on April 14, 2014 - Published by Cold Spring Harbor Laboratory Press from


    Skeletal muscle is a highly complex and heterogeneoustissue serving a multitude of functions in the organism.The process of generating musclemyogenesiscan bedivided into several distinct phases (Tajbakhsh 2009). Dur-ing embryonic myogenesis, mesoderm-derived structuresgenerate the first muscle fibers of the body proper, and insubsequent waves additional fibers are generated alongthese template fibers (Parker et al. 2003; Sambasivan andTajbakhsh 2007). In the poorly understood perinatal phase,muscle resident myogenic progenitors initially proliferateextensively but later on decrease as the number of myonu-clei reaches a steady state and myofibrillar protein synthesispeaks (Schultz 1996; Davis and Fiorotto 2009). Once themuscle has matured, these progenitors will enter quies-cence and henceforth reside within in it as satellite cells.Adult skeletal muscle, like all renewing organs, relies on amechanism that compensates for the turnover of ter-minally differentiated cells to maintain tissue homeostasis(Schmalbruch and Lewis 2000; Pellettieri and SanchezAlvarado 2007). This type of myogenesis depends on theactivation of satellite cells that have the potential to differ-entiate into new fibers (Charge and Rudnicki 2004). Themost comprehensively studied form of myogenesis takesplace when mature muscle is damaged and large cohortsof satellite cells expand mitotically and differentiate torepair the tissue and reestablish homeostasis (Rudnickiet al. 2008). Many similarities, such as common transcrip-tion factors and signaling molecules, between embryonicmyogenesis and regeneration in the mature skeletal muscu-lature have been discovered (Tajbakhsh 2009). It is nowgenerally accepted that satellite cells are closely related toprogenitors of somitic origin (Gros et al. 2005; Relaixet al. 2005; Schienda et al. 2006; Hutcheson et al. 2009; Lep-per and Fan 2010). How the uncommitted character, or thestemness, of the embryonic founder cells is retained insatellite cells remains a matter of ongoing investigation.

    A broad spectrum of signaling molecules instructsmyogenesis during embryonic development and in postna-tal life (Kuang et al. 2008; Bentzinger et al. 2010). The acti-vation of cell surface receptors by these signals inducesintracellular pathways that ultimately converge on a batteryof specific transcription and chromatin-remodeling fac-tors. These factors translate the extracellular signals intothe gene and microRNA expression program, which as-signs myogenic identity to the muscle progenitors. Myogen-ic transcription factors are organized in hierarchical geneexpression networks that are spatiotemporally induced orrepressed during lineage progression. Cellular identity dur-ing development is further defined by intrinsic mechanismssuch as the ability to self-renew and the capacity to prevent

    mitotic senescence or DNA damage (He et al. 2009). Theextent of intrinsic and extrinsic contribution during line-age progression from the most ancestral cell to a differenti-ated muscle fiber will vary depending on the respectivestage of cellular commitment but are unlikely to be exclu-sive. The molecular mechanisms that integrate variousenvironmental and inherent controls to establish the char-acter of cells in the myogenic lineage are a matter of intenseresearch, and the recent emergence of powerful tools inmouse genetics has provided significant new insights (Lew-andoski 2007). The following sections review our currentunderstanding of the molecular regulation of muscle for-mation during development and in the adult.


    Signaling molecules, which can function as morphogens,control the genetic networks patterning the structure oftissues in the developing embryo through to the adultorganism (Gurdon and Bourillot 2001; Davidson 2010).Depending on the concentration and distance from thesource, morphogens qualitatively trigger different cellularbehavioral responses (Gurdon et al. 1998).

    2.1 Somitogenesis

    The positions and identities of cells that will form the threegerm layers are determined early in gestation (Arnold andRobertson 2009). The prepatterned embryo subsequentlydevelops the ectoderm, mesoderm, and endoderm. Meso-derm is anatomically separated into paraxial, intermediate,and lateral mesoderm, with respect to position from themidline. In the course of development, local oscillationsin gene expression and morphogen gradients induce pair-wise condensations of paraxial mesoderm into somites,which develop progressively from head to tail (Fig.