Program in Gene Function and Expression; Program in Molecular Medicine
Medical Subject Headings
Animals; DNA, Mitochondrial; Expressed Sequence Tags; Gene Expression Regulation; Ligands; Lipid Metabolism; Mice; Mice, Transgenic; Mitochondria; Models, Statistical; Muscle Fibers, Skeletal; Obesity; Oxygen; PPAR delta; *Physical Conditioning, Animal; Physical Exertion; Protein Structure, Tertiary; Running; Signal Transduction; Time Factors
Genetics and Genomics
Endurance exercise training can promote an adaptive muscle fiber transformation and an increase of mitochondrial biogenesis by triggering scripted changes in gene expression. However, no transcription factor has yet been identified that can direct this process. We describe the engineering of a mouse capable of continuous running of up to twice the distance of a wild-type littermate. This was achieved by targeted expression of an activated form of peroxisome proliferator-activated receptor delta (PPARdelta) in skeletal muscle, which induces a switch to form increased numbers of type I muscle fibers. Treatment of wild-type mice with PPARdelta agonist elicits a similar type I fiber gene expression profile in muscle. Moreover, these genetically generated fibers confer resistance to obesity with improved metabolic profiles, even in the absence of exercise. These results demonstrate that complex physiologic properties such as fatigue, endurance, and running capacity can be molecularly analyzed and manipulated.
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Citation: PLoS Biol. 2004 Oct;2(10):e294. Epub 2004 Aug 24. Link to article on publisher's site