Making muscles burn more fat and less glucose can increase exercise endurance, but could simultaneously increase the risk of type 2 diabetes, scientists have discovered.
The team of researchers from Baylor College of Medicine in the United States and other institutions looked at how mice burn fat. Their muscles use glucose (carbohydrate) as fuel when they are awake and active and switch to fat (lipid) when they are asleep.
The team discovered that disrupting this natural cycle may lead to diabetes but, surprisingly, also can enhance exercise endurance. The switch is controlled by a molecule called histone deacetylase 3, or HDAC3.
The researchers believe that this finding opens the possibility of selecting the right time to exercise for losing body fat but also raises the concern of using HDAC inhibitors as doping drugs for endurance exercise.
‘How the muscle uses glucose is regulated by its internal circadian clock that anticipates the level of its activity during the day and at night,’ said senior author Dr. Zheng Sun, assistant professor of diabetes, endocrinology and metabolism medicine at Baylor.
‘The circadian clock works by turning certain genes on and off as the 24-hour cycle progresses. HDAC3 is a key connection between the circadian clock and gene expression. Our previous work showed that HDAC3 helps the liver alternate between producing glucose and producing lipid. In this work, we studied how HDAC3 controls the use of different fuels in skeletal muscle,’ he explained.
Skeletal muscles, the voluntary muscles, are important in the control of blood glucose in the body. They consume most of the glucose, and if they develop insulin resistance and consequently are not able to use glucose, then diabetes likely will develop. To study the role of HDAC3 in mouse skeletal muscle, the team genetically engineered laboratory mice to deplete HDAC3 only in the skeletal muscles. Then they compared these knocked out mice with normal mice regarding how their muscles burn fuel.
When normal mice eat, their blood sugar increases and insulin is released, which stimulates muscles to take in and use glucose as fuel. ‘When the knocked out mice ate, their blood sugar increased and insulin was released just fine, but their muscles refused to take in and use glucose. Lacking HDAC3 made the mice insulin resistant and more prone to develop diabetes,’ Sun said.
Yet, when the HDAC3 knocked out mice ran on a treadmill, they showed superior endurance, which Sun explained was intriguing because diabetes is usually associated with poor muscle performance. ‘Glucose is the main fuel of muscle, so if a condition limits the use of glucose, the expectation is low performance in endurance exercises. That’s the surprise,’ he pointed out.
The researchers then studied what fuelled the HDAC3 knocked out mice’s stellar performance using metabolomics approaches and found that their muscles break down more amino acids. This changed the muscles’ preference from glucose to lipids and allowed them to burn lipid very efficiently. This explains the high endurance, because the body carries a much larger energy reservoir in the form of lipid than carbohydrate.
The team performed a number of functional genomics studies that established the link between HDAC3 and the circadian clock. ‘In normal mice, when the mouse is awake, the clock in the muscle anticipates a feeding cycle and uses HDAC3 to turn off many metabolic genes. This leads the muscles to use more carbohydrate. When the animal is about to go to sleep and anticipates a fasting cycle, the clock removes HDAC3. This leads the muscles to use more lipid,’ Sun said.
Although these studies were done in mice, the researchers speculate that human muscles most likely follow the same cycle. The study opens the possibility of promoting body fat burning by increasing exercise activity during the periods in which muscles use lipid, which is at night for people.
‘Losing body fat would be easier by exercising lightly and fasting at night. It’s not a bad idea to take a walk after dinner,’ Sun concluded.
The opinions expressed in this article do not necessarily reflect the views of the DiabetesForum.com Community and should not be interpreted as medical advice. Please see your doctor before making any changes to your diabetes management plan.