Stimulation of Slow Skeletal Muscle Fiber Gene Expression by Calcineurin in Vivo

doi:10.1074/jbc.275.7.4545

Stimulation of Slow Skeletal Muscle Fiber Gene Expression by Calcineurin *in Vivo**

From the ^‡Department of Molecular Biology,^¶Pathology, and ^‖Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9148

Abstract

Adult skeletal muscle fibers can be categorized into fast and slow twitch subtypes based on specialized contractile and metabolic properties and on distinctive patterns of muscle gene expression. Muscle fiber-type characteristics are dependent on the frequency of motor nerve stimulation and are thought to be controlled by calcium-dependent signaling. The calcium, calmodulin-dependent protein phosphatase, calcineurin, stimulates slow fiber-specific gene promoters in cultured skeletal muscle cells, and the calcineurin inhibitor, cyclosporin A, inhibits slow fiber gene expression in vivo, suggesting a key role of calcineurin in activation of the slow muscle fiber phenotype. Calcineurin has also been shown to induce hypertrophy of cardiac muscle and to mediate the hypertrophic effects of insulin-like growth factor-1 on skeletal myocytes in vitro. To determine whether activated calcineurin was sufficient to induce slow fiber gene expression and hypertrophy in adult skeletal muscle in vivo, we created transgenic mice that expressed activated calcineurin under control of the muscle creatine kinase enhancer. These mice exhibited an increase in slow muscle fibers, but no evidence for skeletal muscle hypertrophy. These results demonstrate that calcineurin activation is sufficient to induce the slow fiber gene regulatory program in vivo and suggest that additional signals are required for skeletal muscle hypertrophy.

Footnotes

↵* This work was supported by grants from the National Institutes of Health, the Muscular Dystrophy Association, and the Robert A. Welch Foundation (to E. N. O.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵§ Supported by a National Institutes of Health postdoctoral fellowship.
↵** To whom correspondence should be addressed. Tel.: 214-648-1187; Fax: 214-648-1196; E-mail: eolson@hamon.swmed.edu.
↵2 H. Wu, F. J. Naya, T. McKinsey, B. Mercer, R. Bassel-Duby, E. N. Olson, and R. S. Williams, unpublished results.
Abbreviations:

NFAT

nuclear factor of activated T cells

CsA

cyclosporin A

TnI

troponin I

IGF

insulin-like growth factor

MCK

muscle creatine kinase

hGH

human growth hormone

RT-PCR

reverse transcription-polymerase chain reaction

bp

base pair(s)
- Received November 12, 1999.
- Revision received December 11, 1999.
The American Society for Biochemistry and Molecular Biology, Inc.