Effortless Exercise

Researchers at Duke Medical Center and the University of Texas Southwestern Medical Center in Dallas have found a biochemical pathway in muscle cells responsible for generating many of the beneficial effects of regular exercise.

The discovery identifies targets for the development of new drugs that could improve the quality of life in people suffering from chronic illness who could benefit from aerobic exercise but are unable to perform the amount of exercise necessary to produce the desired effects, says R. Sanders Williams M.D. '74, dean of the medical school and senior author of the study. Drugs that stimulate this pathway also could reproduce the health benefits of exercise that help to prevent diabetes and cardiovascular disease. The study appears in the April issue of the journal Science.

The research was conducted at UT Southwestern, where Williams was director of the Ryburn Center for Molecular Cardiology until 2001, when he became medical dean at Duke.

In 1998, Williams and colleagues published findings showing that activating the signaling protein calcineurin could mimic some of the effects of endurance exercise. In the new study, which was funded by grants from the National Institutes of Health, researchers detail the discovery of another cellular signaling pathway involving signaling proteins called calmodulin-dependent that control genes influencing the physiological and metabolic properties of muscles.

Williams and his colleagues have spent twenty years studying why muscle tissues remodel themselves when subjected to different forms of exercise. Skeletal muscle fibers consist of two types: "slow-twitch" muscle that can handle long-term, low-level loads, and "fast-twitch" muscle that responds to abrupt heavy loads. In remodeling, sudden heavy exercise such as weightlifting makes muscles larger, while sustained exercise such as long-distance running alters the fiber-type composition of muscle to increase resistance to fatigue and reduce the risk for diabetes or cardiovascular disease.

The scientists set out to answer a central question of exercise biology: How do muscle cells sense that they are being exercised and translate that signal into changes in gene expression influencing the metabolic properties of muscle?

In the new study, researchers identified a protein enzyme, CaMK, that controls production of mitochondria in mammalian muscle tissue. Mitochondria are the structures within cells that transform oxygen and other molecules into energy for all cellular functions. People who exercise regularly have more mitochrondria in their muscles than those who are sedentary, Williams says. The scientists learned that CaMK triggers a signaling pathway that controls mitochondrial production in mouse cells--meaning that the muscles of sedentary mice assumed the characteristics of muscles of animals that exercised regularly. They also found that CaMK activates a gene that encodes another protein, called PGC-1, which is known to activate hundreds of genes that control the amount of mitochondria in a cell.

"Activation of CaMK recapitulated the effects of exercise, indicating that this is a central pathway by which exercise modifies the metabolic properties of skeletal muscles," Williams says. "Until now, scientists did not suspect that this particular enzyme was involved in that control."

The findings are clinically significant, says Williams, not only because skeletal muscles are necessary for movement, but also because they affect metabolism of sugars and fats that circulate in the blood. The metabolic properties of skeletal muscles will determine one's risk of developing diabetes and other chronic conditions.

"An inability to exercise complicates many chronic medical conditions and makes those conditions worse," he says. "For example, we know that heart-failure patients who exercise regularly feel better and over time acquire a greater capacity to exercise, but many are unable to perform the amount of exercise necessary to produce the favorable effects. One application of this discovery, if it leads to the development of drugs to activate this pathway, would be to help improve the quality of life of people who have such chronic diseases."

A research team at Duke led by Williams is continuing to study the pathway described in this study to identify the best targets for drug discovery. They also seek to determine whether the pathway is pertinent to other tissues such as fat or even to the biology of cancer cells, Williams says. Mitochondria are fundamental to the function of all cells and the pathway that controls mitochondria could possibly be manipulated in other kinds of medical conditions, he says.