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Drugs Boost Exercise Endurance in Mice

Researchers have identified 2 drugs that, in mice, seem to confer many of the healthful benefits of long-term exercise, giving them more fat-burning muscle and better endurance. The scientists say their findings might eventually lead to better treatments for certain muscle disorders, frailty, obesity and other conditions in which exercise is known to be helpful but not always practical.

Scientists have long searched for drugs that mimic or enhance the effects of exercise and its known therapeutic benefits. Four years ago, Dr. Ronald Evans of the Salk Institute and his colleagues identified a potential drug target—a signaling protein known as PPARδ, which regulates several fat-burning genes in muscle cells. The researchers created genetically engineered mice that produced high levels of PPARδ in their muscles. The animals’ running endurance nearly doubled, with their muscles developing more fat-burning, fatigue-resistant muscle fibers than normal mice.

In their latest research, published in the July 31, 2008, advance online edition of Cell, the researchers used drugs, rather than genetic engineering, to enhance the effects of PPARδ and another exercise-related molecule, AMPK. The study was funded in part by 3 NIH components—the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

The scientists first gave oral doses of a PPARδ-activating drug to mice for several weeks. Initial results were disappointing. The drug by itself had no impact on the animals’ running endurance in a treadmill test. However, when the scientists added exercise training to the mix—having the mice run on a treadmill for nearly an hour daily for a month—the treated mice were able to run up to 75% farther than mice that received exercise training alone. The treated mice developed nearly 40% more fatigue-resistant muscle fibers than untreated animals. In addition, gene activity in their muscle cells was strikingly similar to the genetically engineered mice in previous studies.

The researchers also tested the effects of the protein AMPK, which is known to be activated by exercise and is involved in regulating many other genes. The mice received daily doses of the drug AICAR, which activates AMPK. To the scientists’ surprise, 4 weeks of AICAR treatment alone activated exercise-related genes and enhanced running endurance by 44% in sedentary mice. In fact, the drug allowed sedentary animals to run longer and farther than animals that had received weeks of exercise training. “We were blown away that AICAR alone mimicked exercise,” Evans said.

Either drug alone activated a unique subset of exercise-related genes. However, the greatest rise in gene activity occurred when the PPARδ-activating drug was combined with exercise training, which activates AMPK. This drug–exercise pattern of gene activity—dubbed an “endurance gene signature”—led to the greatest improvement in endurance.

Because the muscles of humans and mice use similar genetic pathways, the researchers are optimistic that their findings will eventually lead to improved therapies. Yet they caution that the drugs’ effects on human muscles and endurance are still untested.

—by Vicki Contie