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Exercise Pill Makes Mice More Fit
  "In humans, endurance exercise leads to physiological adaptations in the cardiopulmonary, endocrine, and neuromuscular systems (Jones et al., 2000, Lucia et al., 2001). Although our current investigation focused on skeletal muscle, extramuscular effects of PPAR_, AMPK, and exercise may also contribute to increased endurance.......we found that drug treatment can reduce epididymal fat mass, possibly conferring additional systemic benefits....In addition to increasing performance in athletes, exercise has beneficial effects in a wide range of pathophysiological conditions, such as respiratory disorders, cardiovascular abnormalities, type 2 diabetes, and cancer risk.....In this study, we revealed that synthetic PPAR_ activation and exercise.....provide a robust transcriptional cue that reprograms the skeletal muscle genome and dramatically enhances endurance.....We believe that the strategy of reorganizing the preset genetic imprint of muscle (as well as other tissues) with exercise mimetic drugs has therapeutic potential in treating certain muscle diseases such as wasting and frailty as well as obesity where exercise is known to be beneficial.....
.....In this study, we show that the AMP-mimetic AICAR can increase endurance in sedentary mice by genetically reprogramming muscle metabolism in a PPAR_-dependent manner. We also found that a PPAR_ agonist in combination with exercise synergistically induces fatigue-resistant type I fiber specification and mitochondrial biogenesis, ultimately enhancing physical performance. These changes correlate with an unexpected but interesting establishment of a muscle endurance gene signature that is unique to the drug-exercise paradigm. Such a signature is an outcome of molecular crosstalk and perhaps a physical association between exercise-activated AMPK and PPAR_. These findings identify a novel pharmacologic strategy to reprogram muscle endurance by targeting AMPK-PPAR_ signaling axis with orally active ligands."
Could a Pill Replace Exercise?
Scientists have shown that a drug improves endurance in mice

By Nikhil Swaminathan
Scientific American
Good news for couch potatoes. There may be a pill that lets them watch their TV and get their exercise, too-without moving a muscle. Scientists have found a drug that mimics the effects of a workout by, among other things, increasing the body's ability to burn fat.
The study shows the pill can also increase endurance; lab mice that took it ran more than 40 percent longer on a treadmill than their untreated peers.
"It's tricking the muscle into 'believing' it's been exercised daily," says Ronald Evans, a developmental biologist at the Salk Institute for Biological Studies, in La Jolla, Calif., and co-author of a study published in Cell. "It proves you can have a pharmacologic equivalent to exercise."
In addition to supercharging stamina, the drug, called AICAR, may also be useful in treating debilitating muscular disorders such as muscular dystrophy as well as metabolic diseases such as diabetes, because it also appears to help the body use and remove sugar from the blood more effectively.
Researchers say that AICAR-which is in clinical trials to treat some heart ailments-in essence works by reprogramming muscle, switching it from sugar-burning, fast twitch muscle-which is better for speed and power-into fat-burning, slow-twitch muscle that does not tire as easily.
The key to this transformation is a protein called PPARdelta, which Evan's team previously showed could create so-called high-endurance "marathon mice" if it genetically engineered the animals were genetically engineered to make a lot of it. But, another experimental drug that targeted only PPARdelta had some metabolic benefits, including lowering fatty acids and blood sugar, but it only boosted endurance in mice that were running regularly.
Enter AICAR, which targets a protein called adenosine monophosphate-activated protein kinase (AMPK). AMPK is produced when cells need more energy--as they do when we're exercising--and triggers increased levels of PPARdelta. As a result, researchers thought that AICAR could kick off the process inlieu of exercise.
After four weeks of treatment with AICAR, the mice that took it could run on treadmills nearly 1.5 times as long as untreated animals-and without any training.
Sound too good to be true? It may be. Laurie Goodyear, a n associate professor at Harvard Medical School and an investigator at the Harvard-affiliated Joslin Diabetes Center in Boston, applauded the findings but says no pill can duplicate all of the benefits that exercise has on the body.
Warning to athletes who think popping the pill might give them a leg up on the competition: Evans has developed urine and blood tests designed to detect the drug-so don't get any ideas.
Real Diet Pill? New 'Exercise Pill' Tells Cells To Burn Fat; Works in Mice
ScienceDaily (May 1, 2007) - By giving ordinary adult mice a drug - a synthetic designed to mimic fat - Salk Institute scientist Dr. Ronald M. Evans is now able to chemically switch on PPAR-d, the master regulator that controls the ability of cells to burn fat. Even when the mice are not active, turning on the chemical switch activates the same fat-burning process that occurs during exercise. The resulting shift in energy balance (calories in, calories burned) makes the mice resistant to weight gain on a high fat diet.
The hope, Dr. Evans told scientists attending Experimental Biology 2007 in Washington, DC, is that such metabolic trickery will lead to a new approach to new treatment and prevention of human metabolic syndrome. Sometimes called syndrome X, this consists of obesity and the often dire health consequences of obesity: high blood pressure, high levels of fat in the blood, heart disease, and resistance to insulin and diabetes.
This chemical switch is not the first success Dr. Evan's laboratory has had in being able to turn on the PPAR-d switch in adipose or fat cells, activating local metabolism and increasing the amount of calories burned. As a Howard Hughes Medical Investigator at The Salk Institute's Gene Expression Laboratory, Dr. Evans discovered the role of the gene for PPAR-d, the master regulator of fat metabolism. By permanently turning on this delta switch in mice through genetic engineering, he was able to create a mouse with an innate resistance to weight gain and twice the physical endurance of normal mice. Because they were able to run an hour longer than a normal mouse, they were dubbed "marathon mice."
Subsequent work in the Evans laboratory found that activation of PPAR-d in these mice also suppresses the inflammatory response associated with arthrosclerosis.
But the genetic metabolic engineering that created the marathon mouse is permanent, turned on before birth. While a dramatic proof of concept that metabolic engineering is a potentially viable approach, it offers no help to an adult whose muscles are already formed and who now would benefit greatly from having more active, fat-burning muscles.
That is why the potential of chemical metabolic engineering - possibly a one-a-day pill as opposed to permanent genetic metabolic engineering - is so exciting, says Dr. Evans. In today's society, too few people get an ideal amount of exercise, some because of medical problems or excess weight that makes exercise difficult. Having access to an "exercise pill" would improve the quality of muscles, since muscles like to be exercised, and increase the burning of energy or excess fat in the body. And that would result in less fatty tissue, lower amounts of fat circulating in the blood, lower blood glucose levels and less resistance to insulin, lowering the risks of heart disease and diabetes.
The ability to chemically engineer changes in metabolism also has given the researchers more insight into how the PPAR-d switch works, says Dr. Evans. Genetically engineering changes in metabolism in the marathon mice triggers both increased fat burning and increased endurance. Adult normal mice that receive the drug to switch on PPAR-d show increased fat burning and resistance to weight gain, but they do not show increased endurance. Dr. Evans says this suggests the delta switch can operate in different modes, and the laboratory is in the process of figuring out exactly how. He hopes his strategy will make it possible.
Dr. Evan's Experimental Biology presentation on April 30 is part of the scientific program of the American Society for Biochemistry and Molecular Biology.
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