Marathon Mice and PPARd

Press release from The Salk Institute. It is intriguing that any connection is made between this work and athletic performance. Clearly, the scientist's work is aimed at medical intervention and yet the prospects for athletes are implied through the communication. It is a further indication of how the application of pharmaceuticals to sports is sexy enough to spice up scientific research, but that most scientists are not really alarmed by how their work might be used for non-therapeutic purposes. Equally, perhaps Dr Evans is working with WADA to ensure they have tests for any future product that might arrive on the market. While I don't think that this would be enough to deal with the use of dangerous substances in sport, it would be an important development.

Altering steroid receptor genes creates fat burning muscles, resistance to weight gain, and lowered inflammation.

April 04, 2005 La Jalla, CA — The Salk Institute scientist who earlier discovered that enhancing the function of a single protein produced a mouse with an innate resistance to weight gain and the ability to run a mile without stopping, has found new evidence that this protein and a related protein play central roles in the body's complex journey to obesity and offer a new and specific metabolic approach to the treatment of obesity related disease such as Syndrome X (insulin resistance, hyperlipidemia and atherosclerosis).

Dr. Ronald M. Evans, a Howard Hughes Medical Investigator at Salk Institute's Gene Expression Laboratory, presented two new studies Monday, April 4, at Experimental Biology 2005 in the scientific sessions of the American Society for Biochemistry and Molecular Biology.

The studies focus on genes for two of the nuclear hormone receptors that control broad aspects of body physiology, including serving as molecular sensors for numerous fat soluble hormones, Vitamins A and D, and dietary lipids.

The first study focuses on the gene for PPARd, a master regulator that controls the ability of cells to burn fat. When the "delta switch" is turned on in adipose tissue, local metabolism is activated resulting in increased calorie burning. Increasing PPARd activity in muscle produces the "marathon mouse," characterized by super-ability for long distance running.

Marathon mice contain altered muscle composition, which doubles its physical endurance, enabling it to run an hour longer than a normal mouse. Marathon mice contain increased levels of slow twitch (type I) muscle fiber, which confers innate resistance to weight gain, even in the absence of exercise.

Additional work to be reported at Experimental Biology looks at another characteristic of PPARd: its role as a major regulator of inflammation. Coronary artery lesions or atherosclerosis are thought to be sites of inflammation.

Dr. Evans found that activation of PPARd suppresses the inflammatory response in the artery, dramatically slowing down lesion progression. Combining the results of this new study with the original "marathon mouse" findings suggests that PPARd drugs could be effective in controlling atherosclerosis by limiting inflammation and at the same time promoting improved physical performance.

Dr. Evans says he is very excited about the therapeutic possibilities related to activation of the PPARd gene. He believes athletes, especially marathon runners, naturally change their muscle fibers in the same way as seen in the genetically engineered mice, increasing levels of fat-burning muscle fibers and thus building a type of metabolic 'shield" that keeps them from gaining weight even when they are not exercising.

But athletes do it through long periods of intensive training, an approach unavailable to patients whose weight or medical problems prevent them from exercise. Dr. Evans believes activating the PPARd pathway with drugs (one such experimental drug already is in development to treat people with lipid metabolism) or genetic engineering would help enhance muscle strength, combat obesity, and protect against diabetes in these patients.

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