Science magazine, January 20, 2012

Cellular “Self-eating” may account for some benefits of exercise

Few would contest that exercise is a healthy habit. It strengthens muscles, keeps weight down, and–population studies suggest–protects against diabetes, cancer, and Alzheimer’s disease. Still, the mechanisms behind exercise’s many benefits remain murky.

Beth Levine of the University of Texas Southwestern in Dallas had a hunch that her research interest might help solve the mystery of exercise.  Since 1998 Levine has studied autophagy, the “self-eating” process by which cells recycle used or flawed organelles, membranes, and other internal structures.  She has largely focused on its role in cancer and infectious diseases, but elevated autophagy can, at least in animal models, produce widespread benefits, including protection from diabetes, cancer, and neurodegenerative disease.

Since autophagy’s recycling helps cells meet energy demands, Levine began to wonder whether exercise triggers autophagy, and if that could somehow account for exercise’s benefits. The exercise-autophagy parallel, says Levine, is “one of those things that’s so obvious that it got overlooked.”

No longer. In the December issue of Autophagy, an Italian research team reported the first evidence that exercise induces autophagy in the skeletal muscles of mice. This week, in Nature, Levine, her Dallas colleague Congcong He, and others confirm that observation and extend it much further, documenting that autophagy is required for exercise’s beneficial metabolic effects.

“This paper shows that autophagy really plays a critical role in response to exercise,” says Reuben Shaw, a cancer and diabetes researcher at the Salk Institute in La Jolla, California. “It’s a stronger effect than I would have personally imagined.”

In autophagy, a double membrane encircles target material inside a cell, forming a sphere that then spills its contents into another compartment, the lysosome, where enzymes chop them up so the cell can use it all again (Science, Nov. 25, 2011, p. 1048). Organisms from yeast to humans maintain a background level of autophagy, then boost it under stress. 

Exercise is one such stress, Levine found. Running mice for short periods on a treadmill sharply elevated autophagy in many organs, her group reports. The Italian group documented a similar effect in skeletal muscle of healthy mice as part of a study of mice with a form of muscular dystrophy.

To isolate downstream effects of this exercise-induced autophagy, Levine compared normal mice to mutant mice that have normal background autophagy but don’t induce more when stressed or stimulated. “A very elegant approach,” says University of Virginia exercise physiologist Zhen Yan, who has unpublished mouse data showing that exercise training leads to more autophagy.   

In subsequent work, Levine focused on skeletal muscle. Muscle soaks up around 85% of the glucose derived from food. Strenuous exercise normally lowers glucose and insulin in the bloodstream, but autophagy-impaired mice couldn’t do this nearly as well. On the cellular level, following exercise, the autophagy-impaired mice didn’t relocate a glucose transporter to the cell membrane as do normal mice. Levine’s conclusion: autophagy is necessary for the short-term metabolic benefits of exercise.

To examine exercise’s long-term effects, Levine fattened normal mice and autophagy mutants, which gave both groups a form of diabetes, then put them through two months of daily treadmill workouts. Only the normal mic were able to reverse their diabetes through physical training. Such exercise also brought down elevated cholesterol and triglycerides in these mice, but not in the autophagy-impaired mice. Autophagy may also be required to produce the lasting beneficial effects of exercise in diabetes, concludes Levine.

 How do exercise and autophagy cooperate? Levine found that, after short-term exercise, normal mice activate in muscle the enzyme AMP-activated protein kinase (AMPK) but the autophagy-defective rodents don’t. AMPK reprograms cells to boost energy production and its induction by autophagy, Levine says, could explain how exercise training reverses diabetes.

Exercise training also causes lasting adaptations in muscle, including the replacement of old mitochondria, organelles where cellular energy is generated, with new, fuel-efficient ones—what Yan calls a “cash for clunkers” response.  Yan believes autophagy following exercise training contributes to the mitochondrial upgrade and Levine doesn’t rule that out. “We’re not trying to claim that AMPK activation is the only beneficial effect of exercise-induced autophagy on muscle metabolism, or on other organs, and other aspects of health,” she says. “This is probably the tip of the iceberg.” [Indeed, Levine is now investigating whether exercise-induced autophagy can slow or prevent cancer and neurodegenerative disease.]

Marco Sandri, a researcher at the University of Padova in Italy and an author on the December Autophagy paper, suggests that autophagy activators could treat forms of muscular dystrophy. Might such drugs even act as “exercise pills” for otherwise healthy people? Scientists may have trouble demonstrating safety of such drugs, says Levine, since autophagy is a tightly regulated process, and too much can lead to cell death. But exercise itself seems to safely boosts autophagy, and for the first time since college, Levine has started to work out. “I’ve always known exercise is good for you,” she says, “but when we found that it increases autophagy I finally got a treadmill.”