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GEP constitutes a negative feedback loop with MyoD and acts as a novel mediator in controlling skeletal muscle differentiation

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Abstract

Granulin-epithelin precursor (GEP) is an autocrine growth factor that has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation. Here we report that GEP was expressed in skeletal muscle tissue and its level was differentially altered in the course of C2C12 myoblast fusion. The GEP expression during myoblast fusion was a consequence of MyoD transcription factor binding to several E-box (CANNTG) sequences in the 5′-flanking regulatory region of GEP gene, followed by transcription. Recombinant GEP potently inhibited myotube formation from C2C12 myoblasts whereas the knockdown of endogenous of GEP via a siRNA approach accelerated the fusion of myoblasts to myotubes. Interestingly, the muscle fibers of GEP knockdown mice were larger in number but noticeably smaller in size when compared to the wild-type. Mechanistic studies revealed that during myoblast fusion, the addition of GEP led to remarkable reductions in the expressions of muscle-specific transcription factors, including MyoD. In addition, the regulation of myotube formation by GEP is mediated by the anti-myogenic factor JunB, which is upregulated following GEP stimulation. Thus, GEP growth factor, JunB, and MyoD transcription factor form a regulatory loop and act in concert in the course of myogenesis.

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Abbreviations

GEP:

Granulin-epithelin precursor

PCDGF:

P-cell-derived growth factor

FBS:

Fetal bovine serum

GM:

Growth medium

DM:

Differentiation medium

EMSA:

Electrophoretic mobility shift assay

ChIP:

Chromatin immunoprecipitation

PCR:

Polymerase chain reaction

HRP:

Horseradish peroxidase

DAPI:

4, 6-Diamidino-2-phenylindole

MHC:

Myosin heavy chain

COMP:

Cartilage oligomeric matrix protein

TGF-β:

Transforming growth factor-β

TNFα:

Tumor necrosis factor α

Il-1β :

Interleukin-1β

ISH:

In situ hybridization

MCK:

Muscle creatine kinase

HLH:

Helix-loop-helix

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Acknowledgments

This work was funded by NIH research grants AR061484 and AR053210, and a grant from National Psoriasis Foundation (all to C. J. Liu).

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Authors and Affiliations

  1. Department of Orthopedic Surgery, New York University Medical Center, 301 East 17th Street, New York, NY, 10003, USA

    Dawei Wang, Xiaohui Bai, Qingyun Tian, Yongjie Lai, Edward A. Lin, Yongxiang Shi & Chuan-ju Liu

  2. Department of Orthopedics, Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China

    Dawei Wang

  3. Department of Otorhinolaryngology-Head and Neck Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China

    Xiaohui Bai

  4. Stem Cell Research Center, Children’s Hospital of Pittsburgh, Pittsburgh, PA, 15219, USA

    Xiaodong Mu

  5. Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, PA, 15219, USA

    Xiaodong Mu

  6. Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, TX, 75246, USA

    Jian Q. Feng

  7. College of Veterinary Medicine, University of Minnesota, St. Paul, MN, 55108, USA

    Cathy S. Carlson

  8. Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, USA

    Chuan-ju Liu

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  1. Dawei Wang
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Correspondence to Chuan-ju Liu.

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D. Wang, X. Bai, and Q. Tian contributed equally to this paper.

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Wang, D., Bai, X., Tian, Q. et al. GEP constitutes a negative feedback loop with MyoD and acts as a novel mediator in controlling skeletal muscle differentiation. Cell. Mol. Life Sci. 69, 1855–1873 (2012). https://doi.org/10.1007/s00018-011-0901-5

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