Two groups have genetically engineered different pathways that change mice from Sunday morning joggers to Olympic marathoners. Running, like any sustained skeletal muscle activity, consumes large quantities of adenosine triphosphate (ATP), a molecule that fuels many essential cell processes. A number of metabolic pathways supply muscle tissue with the ATP needed to power muscle contraction and sustain ongoing exercise. Which pathway predominates depends on factors like speed, duration, and type of activity, as well as on the availability of oxygen, which fluctuates during activity. Randall Johnson and colleagues have discovered a protein found in skeletal muscle that profoundly influences muscle endurance, while Ronald Evans and colleagues genetically engineer muscle phenotype in a manner that dramatically improves endurance and running performance.

Hypoxia (the physiological state that occurs when oxygen levels drop below normal) governs how ATP is recycled and which energy-producing substrates (for example, glucose or fatty acids) are used; it also generates metabolic by-products, like lactic acid, during strenuous exercise. (Runners know the "lactic acid burn" associated with reduced blood pH.) Glycolysis--the primary source of anaerobic energy in animals--uses glucose, stored as glycogen in muscle cells, to produce ATP. When blood oxygen levels drop, the gene transcription factor hypoxia-inducible factor 1 (HIF-1) triggers the glycolytic pathway.

Randy Johnson and colleagues generated mice that couldn't express HIF-1 in skeletal muscle. Normal and mutant mice went through exercise routines that included swimming and running on treadmills. After exercise, the normal mice had increased levels of gene transcripts and enzymes involved in glucose transport and metabolism. In the mutant mice, expression of these glycolysis associated genes and enzymes was significantly lower. The mutants' ATP levels, however, were normal. Without the molecular machin
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Contact: Paul Ocampo
pocampo@plos.org
1-415-624-1224
Public Library of Science
23-Aug-2004

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