Myostatin promotes the terminal differentiation of embryonic muscle progenitors.

Myostatin, a TGF-beta family member, is an important regulator of adult muscle size. While extensively studied in vitro, the mechanisms by which this molecule mediates its effect in vivo are poorly understood. We addressed this question using chick and mouse embryos. We show that while myostatin overexpression in chick leads to an exhaustion of the muscle progenitor population that ultimately results in muscle hypotrophy, myostatin loss of function in chick and mouse provokes an expansion of this population. Our data demonstrate that myostatin acts in vivo to regulate the balance between proliferation and differentiation of embryonic muscle progenitors by promoting their terminal differentiation through the activation of p21 and MyoD. Previous studies have suggested that myostatin imposes quiescence on muscle progenitors. Our data suggest that myostatin's effect on muscle progenitors is more complex than previously realized and is likely to be context-dependent. We propose a novel model for myostatin mode of action in vivo, in which myostatin affects the balance between proliferation and differentiation of embryonic muscle progenitors by enhancing their differentiation.

[1]  T. P. Smith,et al.  Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle. , 1997, Genome research.

[2]  David Ish-Horowicz,et al.  Expression of a Delta homologue in prospective neurons in the chick , 1995, Nature.

[3]  S. Reed,et al.  Nuclear Accumulation of p21Cip1 at the Onset of Mitosis: a Role at the G2/M-Phase Transition , 1998, Molecular and Cellular Biology.

[4]  B. Langley,et al.  Myostatin, a Negative Regulator of Muscle Growth, Functions by Inhibiting Myoblast Proliferation* , 2000, The Journal of Biological Chemistry.

[5]  M. Buckingham,et al.  The formation of skeletal muscle: from somite to limb , 2003, Journal of anatomy.

[6]  Shahragim Tajbakhsh,et al.  Pax3/Pax7 mark a novel population of primitive myogenic cells during development. , 2005, Genes & development.

[7]  C. Tabin,et al.  Somitic origin of limb muscle satellite and side population cells. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J. Devesa,et al.  Myostatin is an inhibitor of myogenic differentiation. , 2002, American journal of physiology. Cell physiology.

[9]  James M. Roberts,et al.  CDK inhibitors: positive and negative regulators of G1-phase progression. , 1999, Genes & development.

[10]  A. Mansouri,et al.  A Pax3/Pax7-dependent population of skeletal muscle progenitor cells , 2005, Nature.

[11]  Florian Caiment,et al.  A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep , 2006, Nature Genetics.

[12]  Se-Jin Lee,et al.  Regulation of skeletal muscle mass in mice by a new TGF-p superfamily member , 1997, nature.

[13]  Seumas McCroskery,et al.  Myostatin negatively regulates satellite cell activation and self-renewal , 2003, The Journal of cell biology.

[14]  C. Tabin,et al.  Ectopic expression of Sonic hedgehog alters dorsal-ventral patterning of somites , 1994, Cell.

[15]  A. Gossler,et al.  Premature myogenic differentiation and depletion of progenitor cells cause severe muscle hypotrophy in Delta1 mutants , 2007, Proceedings of the National Academy of Sciences.

[16]  Se-Jin Lee,et al.  Regulation of myostatin activity and muscle growth , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  J. Epstein,et al.  RBP-J (Rbpsuh) is essential to maintain muscle progenitor cells and to generate satellite cells , 2007, Proceedings of the National Academy of Sciences.

[18]  S. Elledge,et al.  p21(CIP1) and p57(KIP2) control muscle differentiation at the myogenin step. , 1999, Genes & development.

[19]  R. Ahima,et al.  Functional improvement of dystrophic muscle by myostatin blockade , 2002, Nature.

[20]  C. Marcelle,et al.  In ovo electroporation of avian somites , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[21]  O. Pourquié,et al.  Delta 1-activated notch inhibits muscle differentiation without affecting Myf5 and Pax3 expression in chick limb myogenesis. , 2000, Development.

[22]  A. Bradley,et al.  Multiple defects and perinatal death in mice deficient in follistatin , 1995, Nature.

[23]  K. Patel,et al.  Myostatin imposes reversible quiescence on embryonic muscle precursors , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[24]  C. Marcelle,et al.  A common somitic origin for embryonic muscle progenitors and satellite cells , 2005, Nature.

[25]  C. Marcelle,et al.  A two-step mechanism for myotome formation in chick. , 2004, Developmental cell.

[26]  T. Fielder,et al.  Lower skeletal muscle mass in male transgenic mice with muscle-specific overexpression of myostatin. , 2003, American journal of physiology. Endocrinology and metabolism.

[27]  Se-Jin Lee,et al.  Double muscling in cattle due to mutations in the myostatin gene. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[28]  T. Zimmers,et al.  Induction of Cachexia in Mice by Systemically Administered Myostatin , 2002, Science.

[29]  Chaya Kalcheim,et al.  Lineage analysis of the avian dermomyotome sheet reveals the existence of single cells with both dermal and muscle progenitor fates , 2005, Development.

[30]  John C. McDermott,et al.  Smad7 Promotes and Enhances Skeletal Muscle Differentiation , 2006, Molecular and Cellular Biology.

[31]  Michel Georges,et al.  A deletion in the bovine myostatin gene causes the double–muscled phenotype in cattle , 1997, Nature Genetics.

[32]  Marc S. Williams.  Myostatin mutation associated with gross muscle hypertrophy in a child. , 2004, The New England journal of medicine.

[33]  K. Patel,et al.  The regulation and action of myostatin as a negative regulator of muscle development during avian embryogenesis. , 2002, Developmental biology.

[34]  G. Cabello,et al.  Mechanisms involved in the inhibition of myoblast proliferation and differentiation by myostatin. , 2003, Experimental cell research.

[35]  Yan Chen,et al.  Extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway is involved in myostatin-regulated differentiation repression. , 2006, Cancer research.

[36]  S. Bhasin,et al.  Myostatin inhibits cell proliferation and protein synthesis in C2C12 muscle cells. , 2001, American journal of physiology. Endocrinology and metabolism.

[37]  M. Rudnicki,et al.  The molecular regulation of myogenesis , 2000, Clinical genetics.

[38]  K. Patel,et al.  Follistatin complexes Myostatin and antagonises Myostatin-mediated inhibition of myogenesis. , 2004, Developmental biology.

[39]  B. Langley,et al.  Myostatin Inhibits Myoblast Differentiation by Down-regulating MyoD Expression* , 2002, The Journal of Biological Chemistry.