Making muscles burn more fat and less glucose may increase exercise endurance but simultaneously cause diabetes, a new study has warned. Mouse muscles use glucose (carbohydrate) as fuel when the animals are awake and active and switch to fat (lipid) when they are asleep.
Researchers from Baylor College of Medicine in the US 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. 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 Zheng Sun from 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, said Sun.
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, Sun added.
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, Sun and colleagues 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 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, Sun added.
Researchers studied what fueled the HDAC3-knocked out mices 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 study appears in the journal Nature Medicine.
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