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Molecular and Cellular Biology, December 2004, p. 10777-10791, Vol. 24, No. 24
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.24.10777-10791.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Sp3 Proteins Negatively Regulate ß Myosin Heavy Chain Gene Expression during Skeletal Muscle Inactivity{dagger}

Gretchen Tsika,1 Juan Ji,1 and Richard Tsika1,2,3*

Department of Biochemistry, School of Medicine,2 Department of Biomedical Sciences, School of Veterinary Medicine,1 Dalton Cardiovascular Research Center, University of Missouri—Columbia, Columbia, Missouri3

Received 6 July 2004/ Returned for modification 7 August 2004/ Accepted 24 September 2004

In adult skeletal muscle, ß myosin heavy chain (ßMyHC) gene expression is primarily restricted to slow type I fibers; however, its expression is down-regulated in response to muscle inactivity. Little is known about the signaling pathways and transcription factors that mediate this important functional response. This study demonstrates that increased binding of Sp3 to GC-rich elements in the ßMyHC promoter is a critical event in down-regulation of ßMyHC gene expression under non-weight-bearing conditions. Conversely, binding of Sp3 to these elements decreased while Sp1 binding increased with nuclear extracts from plantaris muscle exposed to mechanical overload, a stimulus that increases ßMyHC gene expression. In addition, these experiments revealed the existence of an Sp4-DNA binding complex when using adult skeletal muscle nuclear extract was used but not when nuclear extracts from cultured myotubes were used. Sp3 proteins are competitive inhibitors of Sp1-mediated ßMyHC reporter gene transactivation in both Drosophila SL-2 and mouse C2C12 myotubes. Sp4 is a weak activator of ßMyHC gene expression in SL-2 cells, which lack endogenous Sp1 activity, but does not activate ßMyHC gene expression in C2C12 myotubes, which have high levels of Sp1. These results suggest that competitive binding of Sp family proteins regulate ßMyHC gene transcription in response to altered neuromuscular activity.

* Corresponding author. Mailing address: University of Missouri—Columbia, Biochemistry E102 Vet Med Bldg., 1600 Rollins Rd., Columbia, MO 65211. Phone: (573) 884-4547. Fax: (573) 884-6890. E-mail: tsikar{at}missouri.edu.

{dagger} This article is dedicated to the memory of Gretchen L. Tsika.

Molecular and Cellular Biology, December 2004, p. 10777-10791, Vol. 24, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.24.10777-10791.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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