August 24, 2004
Mouse Engineered For Marathon Running, Resistance To Obesity

Some researchers at the Salk Institute have developed a transgenic mouse with more slow twitching muscle fibers and a resistance to obesity when fed a high fat diet. (same article here)

LA JOLLA, CA — A molecular switch known to regulate fat metabolism appears to prevent obesity and turns laboratory mice into marathon runners, a Salk Institute study has found.

The discovery of the switch could lead to treatments for obesity and disorders associated with it, such as heart disease and type 2 diabetes. The study, led by professor Ronald Evans and his postdoctoral fellow Yong-Xu Wang, appears in the September issue of the Public Library of Science Biology journal (PLoS Biology). Evans is also an Investigator of the Howard Hughes Medical Institute.

Evans, Wang and team discovered that activation of the switch, a receptor called PPAR-delta, increases the rate at which the body burns fat. This makes PPAR-delta an exciting potential target for drugs that treat diabetes and lipid disorders. The team produced a genetically engineered mouse endowed with the activated form of PPAR-delta in its skeletal muscles. The result was a dramatic increase in "non-fatiguing" or "slow twitch" muscle cells and a mouse capable of running up to twice the distance of a normal littermate without training.

By expressing genes for an activated form of the receptor PPAR-delta, we created a mouse that could, compared to normal mice, run marathons, said Evans. The activated form of PPAR-delta produced muscle fibers that enhanced endurance exercise." By turning on PPAR-delta, the team had produced highly efficient muscle fibers that burned fat more rapidly. As a result, the mice were almost unable to gain weight even in the absence of exercise.

"These muscles also provided resistance to obesity, despite the level of exercise," said Evans. "By manipulating this receptor, it is possible to design treatments that change our muscle makeup and help resist obesity and associated metabolic disorders.

To test the concept, Evans and his team treated normal mice with an experimental drug called GW501516 that activates PPAR-delta. These mice also expressed genes for slow-twitch muscles and gained less weight when given a high-fat diet. This drug is now in the earliest stages of being tested on people for its effects on obesity and other disorders of fat metabolism such as high blood cholesterol.

This experiment underscores the importance of metabolism in fighting obesity and improving fitness, said Evans. Activating the PPAR switch may prevent physical fatigue and enhance the quality of exercise, which may lead to a new class of drugs to promote weight loss and treat diseases arising from an overweight population.

If GW501516 turns out to be safe to use then consider the benefits. The drug may increase your muscle mass, reduce your body fat, lower your cholsterol, and reduce your risk of insulin resistance all at the same time.

A substantial portion of the population of Western nations (and probably other nations as well) will embrace the use of drugs and gene therapy that alters muscle metabolism for health reasons alone. The prospect of competing in athletic competitions will not be the main allure of body engineering for most people. The ability to keep off excess fat, prevent the loss of muscle mass with age, lower cholesterol, and avoid type II insulin-resistant diabetes will together attract more people than the drive to perform better in competitive sports.

The research paper for this report was published in PLoS Biology which offers on-line access at no cost The full research paper drives home the point that upregulation of PPARδ (also spelled above as PPARdelta) made the transgenic mice resistant to obesity.

A number of previous studies have shown that obese individuals have fewer oxidative fibers, implying that the presence of oxidative fibers alone may play a part in obesity resistance. To test this possibility, we fed the transgenic mice and their wild-type littermates with a high-fat diet for 97 d. Although the initial body weights of the two groups were very similar, the transgenic mice had gained less than 50% at day 47, and only one-third at day 97, of the weight gained by the wild-type animals (Figure 4A). The transgenic mice displayed significantly higher oxygen consumption on the high-fat diet than the control littermates (unpublished data). By the end of this experiment, the control littermates became obese, whereas the transgenic mice still maintained a normal body weight and fat mass composition (Figure 4A). A histological analysis of inguinal fat pad revealed a much smaller cell size in the transgenic mice (Figure 4B), due to the increased muscle oxidative capacity. While there was no significant difference in intramuscular glycogen content, the triglyceride content was much less in the transgenic mice (Figure 4C and 4D), which may explain their improved glucose tolerance (Figure 4E). We also placed wild-type C57BJ6 mice on the high-fat diet and treated them with either vehicle or the PPARδ agonist GW501516 for 2 mo. GW501516 produced a sustained induction of genes for type I muscle fibers; this, at least in part, resulted in an only 30% gain in body weight, a dramatically reduced fat mass accumulation, and improved glucose tolerance, compared to the vehicle-treated group (Figure 5). Thus, muscle fiber conversion by stimulation with the PPARδ agonist or the activated transgene has a protective role against obesity.

A synopsis that accompanies the research paper makes the point that most people lack the ideal genetic coding to be a sprinter or to be a marathon runner or both.

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 fiber type ratio (muscle cells are called fibers), 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-meter world record in your lifetime. (In case you'd like to try, that's 9.78 seconds for a man and 10.49 seconds for a woman.)

Of course that doesn't prevent those at the highest levels from using the latest performance enhancer to get that extra 1% edge. But wait until trainers hear about the Marathon Mouse. 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 fibers 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. (For more on muscle fiber metabolism, see synopsis titled “A Skeletal Muscle Protein That Regulates Endurance”) Fast-twitch fibers, which produce ATP through anaerobic glycolysis, generate rapid, powerful contractions but fatigue easily. Top-flight sprinters have up to 80% type II fibers while long-distance runners have up to 90% type I fibers. Coach potatoes have about the same percentage of both.

In the future we are going to be able to use drugs and gene therapy to tune our metabolisms to operate more like the metabolisms athletes who perform best in specific types of sports. But note that we will have to choose how we want to optimize our bodies. An ideal optimization for sprinting will reduce performance in distance running and vice versa.

The drug GW501516 which the Salk team used to upregulate PPARδ may not be causing its main anti-obesity effect by increasing the amount of slow twitch muscle. A different research team at the University of Queensland reports that GW501516 causes changes in lipid metabolism and in energy uncoupling.

Activation of PPARß/δ by GW501516 in skeletal muscle cells induces the expression of genes involved in preferential lipid utilization, ß-oxidation, cholesterol efflux, and energy uncoupling. Furthermore, we show that treatment of muscle cells with GW501516 increases apolipoprotein-A1 specific efflux of intracellular cholesterol, thus identifying this tissue as an important target of PPARß/δ agonists. Interestingly, fenofibrate induces genes involved in fructose uptake, and glycogen formation. In contrast, rosiglitazone-mediated activation of PPAR{gamma} induces gene expression associated with glucose uptake, fatty acid synthesis, and lipid storage

The reference to energy uncoupling suggests that GW501516 and PPARδ might be causing more of the energy that is produced by breaking down sugars to be given off as heat.

Share |      Randall Parker, 2004 August 24 02:58 PM  Biotech Athletics

Darwin said at August 25, 2004 9:53 AM:

Humans rule, animals drool!!




VoiceOfReason said at October 22, 2005 5:32 PM:

Honestly now, if you are going to post an article like that, please do some research. Genetics do not determine what ratio of type-I or type-II muscle a person has. Type-I and type-II muscle ratios are the result of specific training routines. The predominance of type-II in sprinters is the result of speed workouts, and strength training. Speed and strength workouts cause higher levels of type-II or fast twitch muscle, while long distance and endurance training causes smaller, type-I cells to form.

Genetically engineering humans to become the best athlete possible from birth is immoral. Humans are then no longer individual, they are created for entertainment. Genetically engineering humans is the equivalent of giving an athlete drugs to enhance performance, it gives an unfair advantage to the select few that have been helped from before birth.

Third, this study and article advocates unhealthy diets, with the promise of being completely fit. The mouse was given a high fat diet and was still in the "healthy" weight range. More studies would need to be done on the other effects the drug would have on the mice. Just because mice do not gain weight in a high-fat diet, does not mean eating high amounts of fat would not damage heart, liver, and kidney fuction.

Studies like the one above are contributing to the evergrowing obesity in the world, and especially in North America and Europe. They promise miracle drugs. The safest and most reliable way to lose weight is to keep a healthy diet, and to exercise regulary.

Randall Parker said at October 22, 2005 6:20 PM:

Supposed VoiceOfReason,

Training makes a difference. But the gap can not be closed by training alone. Genetic differences cause muscle performance differences.

Twins studies are one source of evidence for this contention.

Differences in muscle fiber com- position among athletes have raised the question of whether muscle structure is an acquired trait or is genetically determined. Studies performed on identical twins have shown that muscle fiber composition is very much genetically determined (Komi & Karlsson, 1979), however there is evidence that both the structure and metabolic capacity of individual muscle fibers can adapt specifically to different types of training.

Training can make individual muscle cells bigger but not alter the ratio of numbers of cells of each type.

Medical geneticists have clearly shown that all muscular properties are subject to inherited influences. Muscle fiber numbers are presumably determined by the second trimester of fetal development (McArdle, Katch, & Katch, 1991) . The genetic contributions to muscle tissue fiber composition and size are significant. However, physical training may play a significant role in modifying fiber size and area, and the relative area composed of Type I (slow twitch, oxidative muscle) and Type II (fast twitch, glycolitic) fibers as well as their metabolic capacities. However, as will be discussed in the sections to follow, the proportion of slow and fast twitch muscle fiber types is genetically determined and can not be influenced by training (Costill, Fink, & Pollack, 1976; Gollnick, et al., 1972; Pette & Staron, 1990). Genetics of blood, arterial blood pressure and heart structure
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