Research shines light on circadian clock in our muscles

The University of Bath has reported that new research published in Proceedings of the National Academy of Sciences (PNAS) from researchers in its Department for Health as well as international colleagues has shown a biological clock at work in muscle cells, which could be an important factor in regulating the metabolism and in the development of diabetes.

Biological clocks trigger the release of the hormone melatonin during sleep, leading to the secretion of digestive enzymes at lunchtime or keep people awake at the busiest moments of the day. A “master clock” in the brain synchronises all the subsidiary ones in various organs.

For this study, researchers funded by the Swiss National Science Foundation (SNSF), found that a circadian clock is also at work in human muscles. This finding could have important implications for healthcare and treatments. It is thought that this system going wrong could be an important factor in the development of Type 2 diabetes.

Researchers from the University of Bath, the University of Geneva, the Université Claude Bernard in Lyon, EPFL, the University of Surrey, and the Nestlé Institute of Health Sciences discovered that levels of lipids contained in muscle cells vary during the day, sometimes favouring one kind of lipid over another.

The team has tested the hypothesis that a biological clock could be at play. Testing on volunteer subjects at the University of Bath, they synchronised every subject’s master clock by prescribing them identical light periods as well as meals and exercise time for up to two days. Every four hours, researchers took a very small sample of thigh muscle tissue and analysed its lipid composition.

For the study, the first of its kind, volunteers stayed in labs at the University of Bath for thirty seven hours consecutively. Throughout their stay they were kept in a rested state whilst receiving hourly feedings during waking hours to meet energy requirements, before sleeping from 10pm to 7am. Every four hours researchers took a very small sample of muscle tissue from the thigh and analysed its lipid composition to see how it varied over the course of a typical twenty four hour period.

Dr James Betts, who led the work at the University of Bath, said “We realised we were ideally placed to sample serial muscle biopsies every 4 hours throughout the day and night, thus providing the first evidence of these important biological rhythms in human skeletal muscle.”

The team at Bath also involved Dr Jean-Philippe Walhin and Iain Templeman.

With the samples obtained, the team observed a clear correlation between the muscle cell’s lipid composition and the time of day, explained Howard Riezman, who co-directed the study in Geneva with colleague Charna Dibner. He said “As the combination of lipids varied substantially from one individual to another, we needed further evidence to corroborate these findings.”

In a second step, the researchers switched to an in-vitro experiment. They cultivated human muscle cells and artificially synchronised them in the absence of a master clock, using a signal molecule normally secreted in the body. This highlighted that the cell’s lipid composition varied at different points in the day. When they disrupted the clock mechanism by inhibiting the responsible genes, this variation in lipid composition was lost.

First author on the paper, Ursula Loizides-Mangold said “We have clearly shown that this variation of lipid types in our muscles is due to our circadian rhythm. But the main question is still to be answered: what is this mechanism for?” She thinks that the biological clock in the muscle, with its impact on the lipids, could help in regulating the cells’ sensitivity to insulin. Lipids, being a component of the cell membrane, influence the molecules’ ability to travel into and out of the muscle cells. Changes in its composition could tune the muscle’s sensitivity to the hormone as well as its ability to take in blood sugar. A low sensitivity of the muscle to insulin leads to insulin resistance, which is known to be a cause of Type 2 diabetes.

Co-director of the study, Chama Dibner, said “Studies strongly suggest a link between circadian clocks, insulin resistance and diabetes development. If we establish a link between circadian mechanisms and type 2 diabetes via lipid metabolism, this could have important therapeutic implications. Thanks to our new tools for studying human muscle cellular clocks in vitro, we now have the possibility to investigate this hypothesis in our next study.”

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