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The Forrest Gump of Mice (Minus the Insipid Adages)

A simple gene switch lets rodents run and run and run.

By Katie Palmer
Oct 26, 2011 5:00 AMNov 12, 2019 5:08 AM


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On November 6, streets in all five boroughs of the Big Apple will be cordoned off and shoelaces will be tightened in preparation for the 42nd annual New York City Marathon. The 26.2-mile course is a grueling test of endurance, but perhaps not for long. Physiologist Tejvir Khurana at the University of Pennsylvania has discovered a gene in mice that allows them to run about three and a half miles on an exercise wheel—more than the equivalent of a mouse marathon—without fatigue. Nor do the mice require external motivation. They appear to run just to run.

The exact mechanism at play is unknown, but Khurana has found dramatic changes in the rodents’ musculature. Endurance athletes rely on slow-twitch muscles, fibrous bundles that guzzle oxygen and fatigue slowly. Sprinters, however, derive their power from fast-twitch fibers that produce intense bursts of energy. These fibers use little oxygen but tire quickly. In mice engineered without a muscle-building gene called IL-15R-alpha, fast-twitch muscles in their front legs acted more like slow-twitch fibers. Despite running for hours every night, the engineered mice showed no exhaustion, whereas unaltered mice bonked after just half a mile.

In humans, variants of the IL-15R-alpha gene have been found in world-class endurance competitors, suggesting a target for gene therapies aimed at boosting the ability to exercise longer. “It’s not unreasonable that athletes would try to improve their performance this way,” says Khurana, who is investigating treatments for muscle-wasting diseases and obesity but often receives inquiries from athletes.

Gene doping is technically possible, which is why the World Anti-Doping Agency preemptively banned the practice among Olympians in 2003. Athletes looking for an edge could theoretically inject DNA swatches into their thighs and hope for a transformation, but not without taking some serious risks. The IL-15R-alpha gene is expressed in tissues other than muscle, and no one knows the full consequences of turning the gene off. Forrest Gump aside, few people would want to run forever.

Reference: Emidio E. Pistilli et al. Loss of IL-15 receptor α alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles. The Journal of Clinical Investigation. 2011;121(8):3120–3132. doi: 10.1172/JCI44945

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