Marathon mice created by gene targeting 24/8/04. By PLoS Biology Increasing the levels of a skeletal muscle protein allows 'marathon mice' to run twice as far as normal mice.

Have you ever noticed that long-distance runners and sprinters seem specially engineered for their sports? One's built for distance, the other speed. The ability to generate quick bursts of power or sustain long periods of exertion depends primarily on your muscle fibre type ratio (muscle cells are called fibres), which depends on your genes.

To this extent, elite athletes are born, not made. No matter how hard you train or how many performance-enhancing drugs you take, if you're not blessed with the muscle composition of a sprinter, you're not going to break the 100-metre world record (9.78 seconds for a man and 10.49 seconds for a woman).

A new study by Ronald Evans and colleagues provides evidence that endurance and running performance can be dramatically enhanced through genetic manipulation.

Skeletal muscles come in two basic types: type I, or slow twitch, and type II, or fast twitch. Slow-twitch fibres rely on oxidative (aerobic) metabolism and have abundant mitochondria that generate the stable, long-lasting supplies of adenosine triphosphate, or ATP, needed for long distance.

Fast-twitch fibres, which produce ATP through anaerobic glycolysis, generate rapid, powerful contractions but fatigue easily. Top-flight sprinters have up to 80 per cent type II fibres while long-distance runners have up to 90 per cent type I fibres. Couch potatoes have about the same percentage of both.

Endurance training can enhance the metabolic performance of muscle types, and now it appears that training can also induce conversion between fibre types. Specific changes in gene expression trigger this oxidative fibre transformation, but the transcription factor responsible for engineering this shift was unknown. Evans and colleagues suspected that a nuclear receptor called PPAR-delta – a major regulator of fat burning in fat tissue that is also prevalent in skeletal muscle – might be involved.

To investigate this possibility, the authors genetically engineered mice to express an activated form of the PPAR-delta protein in skeletal muscle. Type I fibres normally express higher levels of PPAR-delta than type II fibres, and the transgenic mice showed much higher levels of the protein than their normal littermates. The transgenic mice also had much redder muscles than the controls – type I fibres have high levels of myoglobin, the red-pigmented protein that facilitates the movement of oxygen within muscle – and elevated levels of proteins associated with mitochondrial biogenesis and operation.

A final line of evidence indicating a type I fibre switch was the elevated level of specialised type I contractile proteins and decreased level of specialised type II contractile proteins in the transgenic mice. Interestingly, these same results were seen when naturally occurring (endogenous) PPAR-delta levels were stimulated in the normal mice (with an orally active compound). This suggests that muscle fibres can be transformed into type I endurance fibres by simply activating the endogenous PPAR-delta pathway.

In a weight-conscious world, oxidative fibres are thought to offer resistance against obesity since obese individuals have fewer type I fibres than average-weight individuals. Sure enough, transgenic mice fed a high-fat diet gained far less weight than normal mice fed the same diet, even in the absence of exercise. The transgenic mice had much smaller fat cells, which the authors attribute to enhanced oxidative capacity of the muscle tissue, and improved glucose tolerance. (Obese individuals lose the ability to metabolise glucose, which puts them at risk for diabetes.) But what about performance? Remarkably, the marathon mice ran about an hour longer than controls, showing dramatic improvement in both running time and distance – increases of 67 per cent and 92 per cent, respectively.

Altogether, these results show that PPAR-delta drives the conversion of type I muscle fibres by activating pathways that enhance physical performance and 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. A full understanding of the molecular basis of muscle fibre determination, including the interactions between PPAR-delta and its regulatory components, awaits further study.

Article adapted from the Public Library of Science Biology synopsis.

Further reading

Wang Y X, Zhang C L, Yu R T, Cho H K, Nelson M C, et al. Regulation of muscle fibre type and running endurance by PPAR-delta. PLoS Biol 2004 2(10): e294. Full text , synopsis .