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Molecular and Cellular Biology, October 2003, p. 6725-6738, Vol. 23, No. 19
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.19.6725-6738.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Role of Metalloprotease Disintegrin ADAM12 in Determination of Quiescent Reserve Cells during Myogenic Differentiation In Vitro{dagger}

Yi Cao,{ddagger} Zhefeng Zhao, Joanna Gruszczynska-Biegala, and Anna Zolkiewska*

Department of Biochemistry, Kansas State University, Manhattan, Kansas 66506

Received 29 January 2003/ Returned for modification 17 March 2003/ Accepted 30 June 2003

Skeletal myoblasts grown in vitro and induced to differentiate either form differentiated multinucleated myotubes or give rise to quiescent, undifferentiated "reserve cells" that share several characteristics with muscle satellite cells. The mechanism of determination of reserve cells is poorly understood. We find that the expression level of the metalloprotease disintegrin ADAM12 is much higher in proliferating C2C12 myoblasts and in reserve cells than in myotubes. Inhibition of ADAM12 expression in differentiating C2C12 cultures by small interfering RNA is accompanied by lower expression levels of both quiescence markers (retinoblastoma-related protein p130 and cell cycle inhibitor p27) and differentiation markers (myogenin and integrin {alpha}7A isoform). Overexpression of ADAM12 in C2C12 cells under conditions that promote cell cycle progression leads to upregulation of p130 and p27, cell cycle arrest, and downregulation of MyoD. Thus, enhanced expression of ADAM12 induces a quiescence-like phenotype and does not stimulate differentiation. We also show that the region extending from the disintegrin to the transmembrane domain of ADAM12 and containing cell adhesion activity as well as the cytoplasmic domain of ADAM12 are required for ADAM12-mediated cell cycle arrest, while the metalloprotease domain is not essential. Our results suggest that ADAM12-mediated adhesion and/or signaling may play a role in determination of the pool of reserve cells during myoblast differentiation.

* Corresponding author. Mailing address: Department of Biochemistry, Kansas State University, 104 Willard Hall, Manhattan, KS 66506. Phone: (785) 532-3082. Fax: (785) 532-7278. E-mail: zolkiea{at}ksu.edu.

{dagger} This is contribution 03-260-J from the Kansas Agricultural Experiment Station.

{ddagger} Present address: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.

Molecular and Cellular Biology, October 2003, p. 6725-6738, Vol. 23, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.19.6725-6738.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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