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Wednesday, July 20, 2011

Missing Gene Helps Mice Run for Hours

Lab mice usually take only an occasional jaunt on their exercise wheels. But mice missing a gene called IL-15Rα run for hours each night, a new study reveals. And the gene doesn't just make a difference to mice—it might also be linked to the ability of long-distance athletes to outperform the rest of us.

Previous studies had suggested that IL-15Rα is important for muscle strength. In experiments on cells grown in a Petri dish, the gene seemed to control the accumulation of proteins necessary for muscle contraction. But IL-15Rα had never been studied in a living animal.

In the new research, physiologist Tejvir Khurana of the University of Pennsylvania and his colleagues genetically engineered mice to lack the IL-15Rα gene. The changes were dramatic. Each night, according to sensors on the wheels in the mice's cages, the modified mice ran six times farther than normal mice.

But these behavioral quirks weren't quite enough to convince Khurana of the effect on muscles. Lack of the IL-15Rα gene could just be making the mice jittery or giving them extra energy. So the researchers dissected muscles from the longer-running mice. The muscles sported increased numbers of energy-generating mitochondria and more muscle fibers, indicating that they tired less easily. And when the researchers stimulated them with electricity, the muscles continued to contract for longer than normal, taking longer to use up their energy stores, the team reports today in The Journal of Clinical Investigation.

Mice, like humans, have two types of muscles. Fast-twitch muscles, such as the muscles in our fingers, allow more precise movements but tire faster, whereas slow-twitch muscles, like those in our back, are more resistant to fatigue but don't allow such precise movements. Removing the IL-15Rα gene, Khurana says, coaxed the mice's fast-twitch leg muscles to turn into slow-twitch muscles.

To study whether IL-15Rα might also affect human endurance, Khurana collaborated with a group of researchers in Australia who keep a library of genetic samples from Olympic and world-class athletes. They found that certain variants of the IL-15Rα gene were more common in endurance athletes like long-distance cyclists and rowers than they were in sprinters. More than three-quarters of long-distance triathletes had one type of variant, for example. Although researchers don't know yet what functional differences the gene variants might have, the finding suggests that the most successful endurance athletes might have a variant that gives their muscles extra endurance.

Biologist Ronald Evans of the Salk Institute for Biological Studies in San Diego, California, says the new study adds to the picture of how endurance is controlled at a molecular level. Evans has characterized the effects of a separate protein called PPARδ, which gives mice extra running endurance as well as enhanced fat-burning abilities. Mice lacking IL-15Rα showed an increase in PPARδ activity, though it's not clear whether the genes directly interact and work through the same mechanisms.

Psychological factors could also be at play. "In a case like this, it's hard to know how to connect the hyperactivity component to the endurance component," Evans says. Even if the mice's muscles have extra endurance, he says, why do they voluntarily run so much more than normal mice?

Still, Khurana says the work raises the possibility that drugs blocking IL-15Rα could one day enhance endurance. Of course, researchers don't know whether such a drug would have other side effects, because the IL-15Rα gene is expressed in many tissues in the body, not just muscles. So for now, if you want to become a better athlete, it's probably best to just lace up your sneakers and get some old-fashioned exercise.

Pistilli1 EE, Bogdanovich S, Garton F, Yang N, Gulbin JP, Conner JD, Anderson BG,Quinn LS, North K, Ahima RS, Khurana1 TS (2011) Loss of IL-15 receptor α alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles J Clin Invest. doi:10.1172/JCI44945.

IL-15 receptor α (IL-15Rα) is a component of the heterotrimeric plasma membrane receptor for the pleiotropic cytokine IL-15. However, IL-15Rα is not merely an IL-15 receptor subunit, as mice lacking either IL-15 or IL-15Rα have unique phenotypes. IL-15 and IL-15Rα have been implicated in muscle phenotypes, but a role in muscle physiology has not been defined. Here, we have shown that loss of IL-15Rα induces a functional oxidative shift in fast muscles, substantially increasing fatigue resistance and exercise capacity. IL-15Rα–knockout (IL-15Rα–KO) mice ran greater distances and had greater ambulatory activity than controls. Fast muscles displayed fatigue resistance and a slower contractile phenotype. The molecular signature of these muscles included altered markers of mitochondrial biogenesis and calcium homeostasis. Morphologically, fast muscles had a greater number of muscle fibers, smaller fiber areas, and a greater ratio of nuclei to fiber area. The alterations of physiological properties and increased resistance to fatigue in fast muscles are consistent with a shift toward a slower, more oxidative phenotype. Consistent with a conserved functional role in humans, a genetic association was found between a SNP in the IL15RA gene and endurance in athletes stratified by sport. Therefore, we propose that IL-15Rα has a role in defining the phenotype of fast skeletal muscles in vivo.

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