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Nowadays, the prevalence of sedentary lifestyles and high-caloric diets leads to an imbalance between energy intake and spending. Hence, in the last decades, we 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 and skeletal muscles represent 40-50% of the human body weight and are one of the main energy spending tissues in our 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, we 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 our 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 we use for jumping, have fewer mitochondria but more myofibrils to generate force. In humans, the muscles are to some extent affected by training.
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.
The study was recently published in the American Journal of Physiology (Endocrinology and Metabolism, https://doi.org/10.1152/ajpendo.00261.2024). It was performed in collaboration with researchers from other groups at the Taltech Department of Chemistry and Biotechnology (Molecular Neurobiology, Wood Chemistry and Analytical Chemistry), and it was funded by the Estonian Research Council, grant no. PRG1127.
This article was originally published on the webpage of TalTech (Tallinn University of Technology).
If this flex of knowledge about muscles and blood fat has you pumped, don’t let your curiosity go soft! Sprint over to our next article for more heart-smart science and read more about New method to find faster treatment for high blood fat levels!
