Researchers identify key cellular signal that builds endurance in muscles (3/6/2008)

BYU researchers have discovered a key cellular signal that builds enzyme in muscles. Postdoctoral researcher David Thomson (r), was the lead author on the paper, working under the direction of Professor William Winder (l). Undergraduate Natasha Fillmore (center) was one of several coauthors.

Everyone knows that exercise improves endurance - now Brigham Young University scientists have discovered one reason why, pinpointing the enzyme that kickstarts the process. The finding will be important to future efforts to enhance the beneficial effects of exercise, and to possibly extend those benefits to people suffering from ailments such as diabetes and heart disease.

Muscles rely on molecular "power plants" called mitochondria to provide energy during repeated exertion. The more of these power plants a muscle has, the longer and harder it can work, and the more fat and glucose it can burn. Scientists had previously observed that repeated exercise increases the amount of mitochondria in muscles, but they do not know specifically why.

The BYU research team - including three undergraduates - led by exercise scientist William W. Winder found one cellular signal that triggers production of more mitochondria. They stimulated an enzyme repeatedly by injecting mice with a chemical, and the mice developed more mitochondria in their muscles. They found that the enzyme modified and activated yet another protein called CREB, which can serve as a master switch to increase muscle mitochondria. The results are reported in the new issue of the Journal of Applied Physiology.

"Everyone knows that exercise is good for you; we wanted to find out why the more you do it, the better you get at it," Winder said. "One of the good things that happens is that mitochondria increase, and that increases your capacity to exercise longer and harder without fatigue. We were looking for the molecular signals that translate muscle contraction into a better capacity to exercise and a better lifestyle."

Winder has previously reported that this same enzyme, known as "AMPK," is what tells your muscles to start burning fat and glucose when you exercise.

"Will Winder is a world authority on regulation of muscle metabolism in response to exercise," said G. Lynis Dohm, professor of physiology at East Carolina University's School of Medicine, who was not affiliated with the research. "This [new result] is a fundamentally important finding that advances our understanding of how our muscles are able to function during exercise and how they adapt when we do repeated exercise bouts."

Further research is necessary to clearly understand how mitochondria are created in human muscle tissue. Clinical researchers have built on Winder's previous studies to explore possible ramifications in improving health. Of course, everyone could receive the health benefits of burning fat and glucose by simply exercising, acknowledged the lead author on the paper, BYU postdoctoral researcher David M. Thomson.

"We would just be understanding how it works," he said. "But not everyone can exercise, and many people have diseases that prevent them from benefiting from regular exercise."

Thomson pointed out that if diabetics can generate more mitochondria and burn more fats, other researchers say, they may also increase their muscles' sensitivity to insulin and therefore burn more glucose as well. Burning more fat could also have implications for heart disease, where the buildup of lipids over time in the heart can cause blockages.

Future implications aside, Winder emphasizes that "this [finding] is simply another reason you should exercise. Exercise is the best, best way to improve and maintain health."

Thomson, who worked as a student athletic trainer for BYU's football and basketball teams when he was an undergraduate, tries to practice what he researches by leading the laboratory team in weekly volleyball matches. Aiding him and Winder on the paper were undergraduate coauthors Natasha Fillmore, Hoon Kim and Jacob Brown, as well as master's candidate Seth Herway. BYU physiology professor Jeffrey Barrow is also a coauthor.

In addition to better illuminating what goes on in muscles during exercise, the study also identified a possible role for AMPK in other biological processes. That is because the protein it activates, "CREB," is known to play a role in turning on genes involved in memory, growth, energy, and reproductive functions. Researchers who study those processes will now test AMPK's significance in influencing them.

Washington University School of Medicine Professor John Holloszy said these findings are "extremely important" because they explain how AMPK "regulates expression of a wide range of genes."

"CREB is a protein that has been studied extensively in many different processes, but how it works isn't very well understood," Winder said. "It's found in so many different parts of the body - just the fact that AMPK can turn it on is going to be something people are going to want to look at."

In fact, one of Winder's BYU colleagues, Allan Judd, has begun preliminary work on the enzyme's potential role in the production of cortisol by the adrenal gland.

Winder and Thomson are continuing to examine the role of AMPK - and other proteins that activate it - in muscle. Their work is funded by a $320,000 grant from the National Institutes of Health.

Note: This story has been adapted from a news release issued by BYU

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