Chemical boosts endurance in mice by 70%
Scientists have identified a chemical compound that boosts physical endurance in mice by 70% without need for exercise. Beyond the obvious applications, the researchers hope the compound will help people with heart conditions, pulmonary disease, type-2 diabetes and other health limitations to achieve – pharmacologically – the benefits of exercising.
The study, published last week in the journal Cell Metabolism, was conducted by a team of researchers at the Salk Institute (San Diego, CA, U.S.). Endurance is the ability to sustain aerobic activity for long periods of time. As people become fitter their muscles ‘learn’ to burn fat rather than carbohydrates (glucose). With this premise, the researchers of the study started looking for ways to chemically increase the body’s ability to burn fat in the same way physical exercise does. “It’s well known that people can improve their aerobic endurance through training,” says senior investigator Ronald Evans. “The question for us was: how does endurance work? And if we really understand the science, can we replace training with a drug?”
In previous work, Evans’ group was able to identify a gene, called PPAR delta (PPARδ), which seemed to be associated with physical fitness. Mice which had the gene permanently activated became ‘long-distance runners’, as well as more resistant to weight gain and highly responsive to insulin – typical traits of fit individuals. They then developed a chemical compound, called GW1516 (GW), which was able activate the PPARδ gene pathway and produce the same results. However, in the first study they found GW was effective only if coupled with physical exercise, which defeated the purpose.
In the current study though, the team gave ‘sedentary’ mice higher doses of GW and for a longer period (8 weeks instead of 4); they found out that while mice in the control group could run about 160 minutes before exhaustion, mice on the drug could run in average 270 minutes – 70% longer. In both groups, exhaustion set in when blood sugar (glucose) dropped to ~70 mg/dl, suggesting that low glucose levels (hypoglycemia) are responsible for fatigue.
To understand the results the researchers examined the gene expression in a major muscle group of the two sets of mice and found that 975 gene changed in response to the drug – either becoming more or less expressed. The genes whose expression increased were associated to breaking down fat for energy, while those which were suppressed were related to breaking down carbohydrates. This suggests that the PPARδ pathway is associated with sugar not being used as energy source in muscles during exercise and possibly being preserved for the brain – which also explains why athletes who hit the proverbial ‘wall’ experience both physical and mental fatigue when they use up their supply of glucose.
“This study suggests that burning fat is less a driver of endurance than a compensatory mechanism to conserve glucose,” says Michael Downes, co-senior author of the paper. “PPARδ is suppressing all the points that are involved in sugar metabolism in the muscle so glucose can be redirected to the brain, thereby preserving brain function.” “Exercise activates PPARδ, but we’re showing that you can do the same thing without mechanical training. It means you can improve endurance to the equivalent level as someone in training, without all of the physical effort,” concluded Weiwei Fan, a Salk research associate and the paper’s first author.
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