Exercise is good for health — but why? A study in rats offers insight

It’s widely known that exercise is beneficial for health. Yet science doesn’t have a clear understanding of what makes moving so good for us, including what molecular mechanisms are activated by exercise.

To answer those questions, researchers launched a large, 10-year study in 2015 to understand the biological impact of physical activity in both rats and humans. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) — a group including scientists from Stanford University, the Broad Institute of MIT and Harvard, and more — published its first paper on Wednesday in Nature.

To start, the group attempted to unravel the impact of endurance exercise in rats, organ by organ. Six-month-old rats trained on a miniature treadmill for one to eight weeks. Two days after their last bout of exercise, researchers measured the molecular response in 19 of their organs and tissues.

“A ridiculous number of measurements — 215 million measurements — were made with all different kinds of molecular assays,” said corresponding author Michael Snyder, the director of the Center for Genomics and Personalized Medicine and Stanford School of Medicine. “The goal is to see the changes that occur.”

Compared to tissues from age- and sex-matched rats who hadn’t exercised, the athletes saw certain molecular responses activated, including immune, metabolic, stress, and mitochondrial pathways. Immune-related pathways were strengthened in the small intestine, for example, as well as, more moderately, in the heart and brain. For rats analyzed in the early stages of training, the researchers saw markers of increased muscle protein turnover in the kidney, as well as higher cortisol levels, likely associated with the physical stress of training.

“It’s a bit like a map,” said Snyder. “We’re trying to make a map of what happens when you exercise, and give a very comprehensive view.”

Exercise also impacted rats differently depending on their sex, a result that didn’t surprise Aaron Baggish, a professor of medicine at University of Lausanne. “We know from decades’ worth of observing both animal and human models that men and women don’t necessarily respond similarly to exercise,” said Baggish, who was not involved in the study. “It’s going to be the work of many of us in this field to try to understand why some of those differences occur, and these molecular data really represent an opportunity to do that in a new way.”

The next MoTrPAC paper, planned for next year or later, is expected to look at human responses to both endurance and resistance training, analyzing blood, muscle, and adipose tissues. But rat modeling is important, said Snyder, because it allows a deep understanding of molecular correlates of exercise that can’t be easily analyzed in humans. “It’s going to become a reference for other studies,” he said.

If the consortium’s studies show similar effects in human and rat tissues, they could be used to develop hypotheses for future human studies. “Many of the findings can be directly translated to humans or are correlated with already known biology in humans,” said Hasmik Keshishian, a senior group leader at the Proteomics Platform of the Broad Institute, and one of the study’s proteomics investigators.

“I think most of us see MoTrPAC as not a means to an end, but really the next step in the puzzle,” said Baggish. “It’s not going to directly link molecules with any specific health outcomes, but it’s going to really open up the door for a lot of more focused studies.”

By helping researchers understand which biological pathways are turned on by exercise, said Baggish, “we will ultimately have a sense of which types of diseases are more or less responsive to exercise.” And with a better understanding of exercise’s physiological effects, physicians could one day prescribe physical activity regimens to tackle specific conditions like metabolic dysfunction-associated steatotic liver disease, inflammatory bowel disease, and cardiovascular disease.