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Exercise Performance in Mice Depends on Circadian Rhythms

The body’s circadian rhythms control a lot more than daily sleep-wake cycles. In fact, these biological mechanisms, often referred to as the circadian clock, exist in nearly every cell in the body and are involved in many important body functions, such as temperature, hunger and hormone release.

Now scientists at The Scripps Research Institute (TSRI) have shown that these rhythms also play a key role in exercise speed and endurance. The finding was published today in the journal Cell Metabolism.

“Mice bred to lack certain circadian proteins can run faster than normal mice for short distances, but can’t run as far over longer distances,” said lead scientist Katja Lamia, a TSRI assistant professor in the Department of Molecular Medicine. “Based on our studies, and those of other researchers, we think these proteins are influencing the use of fuel sources in the mice, which affects their exercise performance.”

Keeping Time with Special Proteins

Lamia’s lab has been exploring the underpinnings of circadian rhythms for several years, specifically focusing on the “cryptochrome” proteins, called CRY1 and CRY2, which are known to help regulate the circadian clock.

Study co-author Drew Duglan, a postdoctoral researcher in Lamia’s lab, describes circadian rhythms as an internal clock, controlled by proteins, that fluctuate in number and activity throughout the 24-hour day. “It allows an organism like mice or you and me to anticipate and respond to our environment -- light and dark, temperature, food availability,” he said. It also affects the body’s organs, metabolism and many other functions.

“There’s even a clock in your liver that regulates the production and secretion of glucose depending on the time of day,” Lamia noted.

A New Role for Circadian Proteins in Exercise

In this latest work, Lamia and her team focused on how the CRY1 and CRY2 proteins might impact exercise capabilities through their interaction with the PPAR-delta protein. The PPAR-delta protein has been the subject of intense research interest over the last decade following a 2004 finding by Ronald Evans at the Salk Institute for Biological Studies, which showed that boosting the protein caused a major increase in exercise endurance in mice. In Evans’s studies, mice engineered to have enhanced PPAR-delta activity could run twice as far as normal mice. The treated mice also shifted from burning glucose for energy to burning fat. The heavier reliance on slow-burning fat gave the mice sustained energy and greater exercise endurance. Evans is a co-author on the TSRI study.

“We knew from the work of Ron Evans’s lab that this protein (PPAR-delta) can really drive exercise performance,” said Lamia. “We wondered if the CRY proteins might also affect exercise physiology, since we found that the CRY proteins can inhibit PPAR-delta[KL1] .”

To explore this question, Lamia’s lab genetically engineered mice to lack the CRY1 and CRY2 proteins and then conducted treadmill tests of the mice against a control group of normal mice. The mice lacking the two proteins ran about 20 percent faster than the normal mice in treadmill tests over short distances. However, the treated mice ran the same distance or perhaps slightly less than the normal mice in endurance tests involving treadmill running for longer periods at a slower pace.

The researchers believe the removal of the CRY proteins, and their suppressive effects, hampers some, but not all of the PPAR-delta’s actions. “The mice burned more fat, but they didn’t conserve glucose. They are burning more of everything (both energy sources).”

Lamia said the research suggests that time of day may influence the body’s fuel use during exercise.

“The CRY proteins only express at certain times of day,” she said, noting this may limit their inhibitory effects on PPAR-delta’s activities to specific periods. “In theory, this could affect speed and endurance at those times and possibly impact performance.”

The researchers noted that the study reinforces the need for further exploration of circadian mechanisms.

“The sleep-wake cycle is just one aspect of the circadian clock, one that people understand,” said study co-author Anna Kriebs, a graduate student in Lamia’s lab. “But underneath that, down to the cellular and molecular level, there are all kinds of physiological outputs that are affected by circadian rhythms, such as metabolic pathways that can influence obesity. These, and many other (biological) aspects, are very important to our health.”

The study, “CRY1/2 selectively repress PPARδ and limit exercise capacity” was supported by the National Institutes of Health (grant K01 DK090188) and (grant R01 DK097164). In addition to Lamia, Duglan and Kriebs, of TSRI, and Ronald Evans of the Salk Institute, authors of the study include: Sabine D. Jordan (first author), formerly of TSRI, now at Neurocrine; Anastasia Kralli, formerly of TSRI, now at Johns Hopkins University, Megan Vaughan, Anne-Laure Huber, Stephanie J. Papp, Madelena Nguyen, Megan Afetian, all of TSRI; Emma Henriksson, formerly of TSRI, now at Novo Nordisk, Denmark; Weiwei Fan, Michael Downes and Ruth T. Yu of the Salk Institute.


 [KL1]This is also included in this study.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see www.scripps.edu.

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Katja Lamia, TSRI assistant professor in the Department of Molecular Medicine and Sabine Jordan, first author. (High-res image)


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