Is genetic engineering endurance the future of the Olympics?

Main Category: Biology / Biochemistry
Article Date: 24 Aug 2004 - 0:00 PDT

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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 1á (HIF-1á) triggers the glycolytic pathway.

Randy Johnson and colleagues generated mice that couldn't express HIF-1á 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 machinery to engage anaerobic metabolism, their muscles switched to aerobic pathways.

During endurance tests, the mutants could swim and run uphill longer than the normal mice, but when it came to running downhill, the normal mice prevailed. Downhill running, it turns out, favors glycolytic metabolism; uphill running and swimming favor oxidative pathways, which the mutants were predisposed toward. But their inappropriate use of this pathway came at a cost. By the final day of a four-day exercise routine, the mutants' run time was significantly shorter and their muscles were clearly damaged.

Ronald Evans and colleagues take a different approach to genetically engineering endurance. Skeletal muscles come in two basic types: type I, or slow twitch, and type II, or fast twitch. Slow-twitch fibers rely on oxidative (aerobic) metabolism and have abundant mitochondria that generate the long-lasting supplies of ATP, needed for long distance. Fast-twitch fibers, which produce ATP through anaerobic glycolysis, generate rapid, powerful contractions but fatigue easily. Top-flight sprinters have up to 80% type II fibers while long-distance runners have up to 90% type I fibers. Couch potatoes have about the same percentage of both.

Endurance training can enhance the metabolic performance of muscle types probably by inducing conversion between fiber types, which is mediated by changes in gene expression. Evans and colleagues suspected that a nuclear receptor called PPARä--a major regulator of fat burning in fat tissue that is also prevalent in skeletal muscle--might be involved and genetically engineered mice to express an activated form of the PPARä protein in skeletal muscle.

The transgenic mice showed much higher levels of the protein, and much redder muscles, than their normal littermates. This suggests that muscle fibers can be transformed into type I endurance fibers by simply activating the endogenous PPARä pathway.

Remarkably, the transgenic ran about an hour longer than controls, showing dramatic improvement in both running time and distance--increases of 67% and 92%, respectively. The genetically engineered conversion of type I muscle fibers not only enhance physical performance but could presumably protect against obesity. The finding that endurance and running capacity can be genetically manipulated suggests that muscle tissue is far more adaptable than previously thought. Maybe Olympiads can be made after all--but don't give up on training just yet.

Note: Due to an embargo break, the embargo time on this release has been lifted.

Citation: Mason S, et al. (2004) Loss of Skeletal Muscle HIF-1a Results in Altered Exercise
Endurance. PLoS Biol 2 (10): e288.

Citation: Wang Y, et al. (2004) Regulation of Muscle Fiber Type and Running Endurance by
PPARd. PLoS Biol 2 (10): e294.

CONTACT:

Randall S. Johnson
University of California, San Diego
9500 Gilman Drive, MC-0377
La Jolla, CA USA
+1-858-822-0509 +1-858-822-5833 (fax)
rjohnson@biomail.ucsd.edu

Ronald Evans
Howard Hughes Medical Institute
The Salk Institute for Biological Studies
10010 N. Torrey Pines Rd.
San Diego, CA USA
+1-858-453-4100 x1302
+1-858-455-1349 (fax)
evans@salk.edu

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