Latest News on Family Medicine April 19, 2019 (3 ​​of 5)


Two articles appearing on April 18 in the journal Cellular Metabolism confirm that the circadian clock is an important factor in how the body responds to physical exertion. The studies focused on different components of the exercise, complementing each other. Based on this work alone, it is too early to tell when it is the best time to run. But at least in the laboratory, exercise at night seems to be more productive, although human lifestyles are much more complicated and therefore this area of ​​research is just beginning.

"It is well known that almost every aspect of our physiology and metabolism is dictated by the circadian clock," says Gad Asher of the Department of Biomolecular Sciences at the Weizmann Institute of Science, senior author of one of the studies. "This is true not only in humans but in all light-sensitive organisms. We decided to ask whether there is a connection between the time of day and performance in exercise."

"Circadian rhythms dominate everything we do," adds Paolo Sassone-Corsi of the University of California's Center for Epigenetics and Metabolism in Irvine, senior author of the other article. "Previous studies from our lab have suggested that at least 50% of our metabolism is circadian, and 50% of our body's metabolites oscillate based on the circadian cycle. It makes sense that exercise is one of the things that is affected."

Both research teams analyzed the association between time of day and performance in exercise, especially in mice. Because mice are nocturnal, one thing they had to do was translate mouse time into human time, distinguishing between the active phase and the resting phase of mice, rather than using numbers on the clock.

Asher's group began by putting mice on mats at different times of the day in their active phase. They examined the exercise capacity of mice at different intensities and exercise regimens and found that overall exercise performance was substantially better (about 50% on average and more on some protocols) compared to mouse night time for the morning hours . These daily differences were decreased in mice that had mutant clocks – supporting a possible role of the clock in the observed variation in exercise performance.

To identify a potential determinant of daily variance in exercise performance, they applied high-throughput and metabolic transcriptomics in muscle tissue. The researchers found that in response to "mouse night" exercise, there were higher levels of a metabolite called ZMP (ribonucleotide 5-aminoimidazole-4-carboxamide). ZMP is known to activate metabolic pathways related to glycolysis and oxidation of fatty acids through the activation of AMPK, which is a major cellular metabolic regulator. Therefore, it is likely to contribute to increased exercise capacity at night. "Curiously, ZMP is an endogenous analog of AICAR [aminoimidazole carboxamide riboside], a compound that some athletes use for doping, "says Asher.

The researchers also studied 12 humans and found similar effects. Overall, people in the study had lower oxygen consumption during exercise at night compared to morning; this translated into better efficiency in the exercise.

The Sassone-Corsi team also put rats on mats, but they had a different approach. Using high-throughput transcriptomics and metabolomics to analyze a wide range of possible factors, they characterized the changes in the muscle tissue of mice that occur in response to exercise. This allowed them to analyze processes such as glycolysis (which contributes to sugar metabolism and energy production) and lipid oxidation (fat burning).

They found that a protein called hypoxia-inducible 1-alpha factor (HIF-1α) plays an important role and that it is activated by exercise in different ways depending on the time of day. HIF-1α is a transcription factor known to stimulate certain genes based on tissue oxygen levels. "It makes sense that HIF-1α is important here, but so far we did not know that its levels fluctuate based on the time of day," says Sassone-Corsi. "This is a new discovery."

Based on the work of the UC Irvine team, exercise appears to have the most beneficial impact on metabolism at the beginning of the active phase (equivalent to the late morning in humans) compared to the resting (night) phase.

Researchers note that while circadian clocks have been preserved throughout evolution, translating the findings into humans is not so simple. One reason is that humans have more variation in their chronotypes than mice living in a laboratory. "You can be a morning person, or you can be a person of the night, and these things should be taken into account," says Sassone-Corsi.

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