By GRETCHEN REYNOLDS New York Times
Two newly published studies investigate the enticing possibility that we might one day be able to gain the benefits of exercise by downing a pill, rather than by actually sweating. But while some of the research holds out promise for an effective workout pill, there remains the question of whether such a move is wise.
The more encouraging of the new studies, which appears this week in Nature Medicine, expands on a major study published last year in Nature. In that study, researchers at the Scripps Research Institute in Jupiter, Fla., reported that a compound they had created and injected into obese mice increased activation of a protein called REV-ERB, which is known to partially control animals’ circadian rhythms and internal biological clocks. The injected animals lost weight, even on a high-fat diet, and improved their cholesterol profiles.
Unexpectedly, the treated mice also began using more oxygen throughout the day and expending about 5 percent more energy than untreated mice, even though they were not moving about more than the other animals. In fact, in most cases, they were more physically lazy and inactive than they had been before the injections. The drug, it seemed, was providing them with a workout, minus the effort.
Intrigued, the Scripps scientists, in conjunction with researchers from the Pasteur Institute in France and other institutions, set out to see what their compound might be doing inside muscles to provide this ersatz exercise. They knew that their drug increased the potency of the REV-ERB protein, but no one yet knew what REV-ERB actually does in muscles. So they began by developing a strain of mice that could not express very much of the protein in their muscle cells.
Those animals proved to be anti-athletes. One of the hallmarks of regular aerobic exercise is that in muscles, it increases the number and vigor of the mitochondria, the cellular structures that help to generate energy while consuming oxygen. But these animals’ muscles contained woefully few mitochondria.
As a result, the animals had diminished endurance, with a maximal oxygen capacity about 60 percent lower than normal. They reached exhaustion on treadmill testing long before their unaffected labmates.
But when, in a separate part of the experiment, scientists added their compound to isolated muscle cells from the deficient mice, the cells began pumping out far more REV-ERB. Those cells, subsequently, began creating large numbers of new mitochondria and strengthening the existing ones.
Finally, the scientists injected their compound into sedentary mice, stimulating their production of REV-ERB beyond what would be considered typical. When they set the sedentary mice loose on little treadmills, they ran “significantly longer both in time and distance” than untreated animals, the authors wrote, even though they had not been training beforehand.
The drug “certainly seems to act as an exercise mimic,” said co-author Thomas Burris, now the chairman of the department of pharmacological and physiological science at St. Louis University School of Medicine. It is not inconceivable, he adds, that at some point in the future, such a drug might allow people, especially those who are disabled or can’t otherwise exercise, to enjoy the health benefits of endurance without the exertion.
But that time is still far distant, with many questions unanswered. It’s still unknown, for example, whether increasing levels of REV-ERB in healthy people is possible, and whether athletes could use the compound to dope. “I have been told” by other scientists who have published data about potential exercise pills “to expect some weird phone calls” from athletes and their support crew, Dr. Burris said.
And a larger concern is whether any single pill can hope to replicate the bogglingly complex physiological effects of physical exercise and whether, in trying to create one, we risk unanticipated consequences.
That issue provided the subtext of the other new study, published this month in PLoS Biology. In it, scientists at Washington University School of Medicine in St. Louis tried to replicate earlier work showing that large doses of resveratrol, the chemical found abundantly in grape skins and red wine, increase the creation of new mitochondria in isolated muscle cells, mimicking aerobic exercise. After those earlier studies, resveratrol, too, had been hailed as a means of counterfeiting exercise pharmacologically.
But the new study punches holes in that hope. When the scientists fed both rats and mice medically tolerable levels of resveratrol in their kibble, the animals did not produce more mitochondria in muscle cells. Only at extremely high doses did resveratrol lead to more mitochondria.
Unfortunately, at these exaggerated doses, the substance has a “toxic effect,” said Dr. John O. Holloszy, a study co-author and professor of medicine at Washington University. It “poisons two of the steps” involved in developing healthy mitochondrial function, Dr. Holloszy said.
Still, the dream of effortless fitness remains alluring. “I know there are probably plenty of people who would prefer” to pop a pill rather than jog a few miles, Dr. Burris said.
But, he adds, the fundamental aim of his and similar research is to aid those who can’t exercise, not those who decline to, and even the beneficiaries inevitably will be short-changed. “Exercise has so many health benefits” and “no drug can” recreate all of them, he concludes. Meaning that a good stroll or swim will probably never be fully reducible to tablet form.