by Estonian Research Council

A larger fraction of AMPK is phosphorylated in oxidative muscles. Credit: TalTech

Nowadays, the prevalence of sedentary lifestyles and high-caloric diets leads to an imbalance between energy intake and spending. Hence, in the last decades, researchers have observed a significant rise in metabolic diseases such as obesity or diabetes.

Activation of AMP-activated kinase (AMPK) is a potential therapeutic target to treat metabolic diseases. Its activation shifts metabolism so that glucose and fatty acids from the diet are used to generate ATP rather than being stored as glycogen and fat.

The heart muscle burns more fat than the calf muscle

The heart and skeletal muscles represent 40–50% of the human body weight and are one of the main energy spending tissues in human bodies. When AMPK in the muscles is activated, it makes the cells take up glucose and fatty acids that are used to generate ATP. In the long-term, AMPK changes gene expression to increase the number of mitochondria that can generate ATP.

AMPK-activating drugs are able to prevent obesity in mice that have diabetes or eat a high-fat diet. However, researchers do not know all the details regarding the regulation of AMPK activation at the cellular level, and this is still being intensely studied.

Researchers from the Laboratory of Systems Biology, Department of Cybernetics at Tallinn University of Technology (TalTech), Estonia, recently found that the extent of AMPK activation is not the same in all muscles. The muscles in the body are different, as they are adapted to the work they perform. Muscles performing continuous work, such as the heart and postural muscles that keep us upright all day, have more mitochondria that make ATP to fuel the work.

In comparison, muscles that perform intense work but tire out quickly, such as the leg muscles used for jumping, have fewer mitochondria but more myofibrils to generate force. In humans, the muscles are to some extent affected by training.

The work is published in the American Journal of Physiology-Endocrinology and Metabolism.

Main author of the science article, Romain Bernasconi Ph.D. student at TalTech, and Kärol Soodla, MA student at TalTech (left in the photo). Credit: TalTech

The more enduring the muscle, the greater the AMPK activation

The new study showed that whereas all muscles express almost the same amount of AMPK, a larger fraction of AMPK is activated in the heart and postural muscles. Thus, the AMPK activation in a muscle depends on what the muscle is used for. Muscles that work for longer periods of time and are more endurant have higher AMPK activation to ensure their uptake of glucose and fatty acids and to maintain their large number of mitochondria and ability to generate ATP.

The mechanism behind this is still under investigation. The study showed that different AMPK-activation did not correlate with the expression of the main activator of AMPK, liver kinase B1 (LKB1). The literature suggests that it does not correlate with the overall levels of AMP.

One way to explain the higher AMPK activation in heart and postural muscles is that the environment inside the cells is not uniform, i.e. muscle cells are not like bags with evenly mixed content. Instead, there are many structures that can form pockets in which the AMP concentration is different from the overall average concentration.

It is possible that more AMPK is activated in heart and postural muscles, because it sits in such pockets and senses AMP concentrations that are higher than average. However, further studies are needed to determine this.

These findings reveal a previously unappreciated complexity in cellular metabolic regulation. By building a more complete picture of basic AMPK regulation mechanisms, this research contributes to the foundation of knowledge upon which more applied studies can later build.

More information: Romain Bernasconi et al, Higher AMPK activation in mouse oxidative compared with glycolytic muscle does not correlate with LKB1 or CaMKKβ expression, American Journal of Physiology-Endocrinology and Metabolism (2024). DOI: 10.1152/ajpendo.00261.2024