CHARACTERISING RHYTHMICITY IN HUMAN SKELETAL MUSCLE METABOLISM

We know that many signals and functions in the body follow a set pattern that repeats everyday (called circadian rhythms). We also know that the timing of this pattern can have an effect on how well our bodies work - for example, shift workers who are active and eat at night when most people are asleep tend to have more health problems such as diabetes and heart disease.

Research using mice shows that these repeating patterns depend on the timing of daily events, like sleep, eating and activity. It is important to study humans as well because mice differ from us both in their behaviour and their metabolism - for example, mice are naturally most active at night and at times when food is limited they become even more active, with the chemistry in mouse muscle responding differently to human muscle.

Muscles are some of the most important body parts for metabolism and health as they use most of the sugar and fat that we eat and have the capacity to dramatically increase our metabolism by moving around (contracting) - and an active lifestyle help us stay healthy. To prepare for this project, we did a pilot study where we took small pieces of muscle from the thighs of human volunteers every few hours for an entire day and night.

We discovered repeating patterns in human muscle, with genetic signals linked to sugar, fat and protein metabolism going up and down every 24 hours. We did this once with people eating in the normal way during the daytime and fasting while asleep at night but also did other studies where we fed people through a tube during sleep - by feeding continuously we removed the acute responses to mealtimes and so could see the underlying rhythms in metabolism, and how they were affected by nutrient availability.

Now that we have seen these patterns in genetic signals, our proven method of collecting human muscle samples for 24 hours whilst feeding continuously (even at night) can be used to study whether those signals actually change how our muscles use carbohydrate and protein over time. We will also be able to find out whether these rhythms in metabolism depend of whether and when the muscle contracts (by asking people to move around at different times of day).

To study cause and effect we will use an experiment where volunteers are randomly divided into three groups: one group will rest for 24 hours, one group will be more active in the morning and the final group will be more active in the evening. We will then be able to see the pattern of metabolism in human muscle for the first time and can compare the muscle samples between the groups to learn about how rhythms in chemical processes are affected by muscle contraction.

As an extra follow-up question, the volunteers will also then continue with their prescribed pattern of rest and activity for two weeks as part of their normal lives, just so we can explore how their muscles and health change in that time.

Our prediction is that there will be clear 24-h rhythms in muscle metabolism, with more carbohydrate and protein taken into muscle to be used or stored earlier in the day. We also think that muscle contractions in the morning will be especially important in driving these rhythmic differences in metabolism over the course of a day.

This research will provide the first information about changes in how our muscles use carbohydrate and protein over time and in relation to our activity patterns. This will improve understanding of how and why daily patterns as sleep, activity, diet and medications can be used to improve human health.