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© The Rockefeller University Press, 0021-9525/1999//633 $5.00
The Journal of Cell Biology, Volume 145, Number 3, , 1999 633-642

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Myogenin Induces a Shift of Enzyme Activity from Glycolytic to Oxidative Metabolism in Muscles of Transgenic Mice



Simon M. Hughes*, Maggie M.-Y. Chi{ddagger}, Oliver H. Lowry{ddagger},{dagger}, and Kristian Gundersen§

* The Randall Institute, King's College London, London WC2B 5RL, United Kingdom; {ddagger} Department of Pharmacology and Molecular Biology, Washington University, St. Louis, Missouri 63110-1093; and § Department of Biology, University of Oslo, Blindern N-0316, Oslo, Norway

Physical training regulates muscle metabolic and contractile properties by altering gene expression. Electrical activity evoked in muscle fiber membrane during physical activity is crucial for such regulation, but the subsequent intracellular pathway is virtually unmapped. Here we investigate the ability of myogenin, a muscle-specific transcription factor strongly regulated by electrical activity, to alter muscle phenotype. Myogenin was overexpressed in transgenic mice using regulatory elements that confer strong expression confined to differentiated post-mitotic fast muscle fibers. In fast muscles from such mice, the activity levels of oxidative mitochondrial enzymes were elevated two- to threefold, whereas levels of glycolytic enzymes were reduced to levels 0.3–0.6 times those found in wild-type mice. Histochemical analysis shows widespread increases in mitochondrial components and glycogen accumulation. The changes in enzyme content were accompanied by a reduction in fiber size, such that many fibers acquired a size typical of oxidative fibers. No change in fiber type-specific myosin heavy chain isoform expression was observed. Changes in metabolic properties without changes in myosins are observed after moderate endurance training in mammals, including humans. Our data suggest that myogenin regulated by electrical activity may mediate effects of physical training on metabolic capacity in muscle.

Key Words: enzymes • exercise • gene expression regulation • mitochondria • muscle fibers

Abbreviations used in this paper: EDL, musculus extensor digitorum longus; MId, Id-1 transgene; MMg, myogenin transgene; MMg + MId, double transgenic mice; MyHC, myosin heavy chain; NRF-1, nuclear respiratory factor 1.

This work was initiated in the laboratory of the late John P. Merlie. We would like to dedicate this paper to him, who died at the peak of his professional life, and to Oliver H. Lowry who was a role model for several generations of scientists. We are grateful to Ms. Alison Maggs for technical assistance and Drs. Jan Henriksson (Stockholm), and Terje Lømo (Oslo) for comments on previous versions of this manuscript.

S.M. Hughes was supported by the Medical Research Council. K. Gundersen was supported by the Norwegian Research Council and the Norwegian Cancer Society.


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