Physical activity is not only important for fitness, but also for health. This is confirmed by a new study conducted under the direction of Prof. Dr. Maximilian Kleinert at the German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE). His team discovered that the protein PanK4 plays a crucial role in the energy metabolism of skeletal muscles. It regulates glucose uptake and fatty acid oxidation and is activated by physical exercise. The study suggests that PanK4 could be a promising approach for the treatment of metabolic diseases such as type 2 diabetes. The results have now been published in the journal Nature Communications.
Skeletal muscles make up around 30 to 40 percent of body weight and are crucial for maintaining a healthy glucose and lipid metabolism. If the skeletal muscles' ability to use or store glucose efficiently is impaired, this can affect glucose homeostasis throughout the body and lead to insulin resistance – a major risk factor for type 2 diabetes. Nevertheless, there are only a few therapy options that focus on the muscles in order to treat metabolic diseases.
Studies on humans and mice
Exercise improves glucose uptake in the muscles and promotes metabolic flexibility, making it an effective way to improve glucose metabolism, especially in cases of insulin resistance and type 2 diabetes. However, the underlying molecular mechanisms are still largely unknown. They were therefore the subject of investigations by a broad-based international research team that was coordinated by Prof. Dr. Maximilian Kleinert, head of the Department of Molecular Physiology of Exercise and Nutrition at the DIfE, and included scientists from the German Center for Diabetes Research (DZD) and others. Using modern mass spectrometry methods, it was possible to identify proteins that are phosphorylated in human and animal muscles as a result of physical exercise. One of these proteins is pantothenate kinase 4 (PanK4).
In order to understand how PanK4 influences energy metabolism in skeletal muscles, Kleinert and his team used various genetic mouse models (knockout and overexpression) with which they carried out physiological studies, such as treadmill studies and glucose tolerance tests. The researchers also examined human muscle tissue taken after training, carried out metabolic analyses and used molecular biology methods such as RNA sequencing and protein analyses.
Mice without PanK4 at a disadvantage
The scientists found that the general lack of PanK4 in mice leads, among other things, to reduced growth and less skeletal muscle mass. In addition, animals which showed a lack of PanK4 specifically in the muscles had an increased fat content and impaired fatty acid oxidation in the muscles. Metabolome analyses showed that PanK4 plays a role in the regulation of acetyl-CoA in the skeletal muscles. The absence of PanK4 led to a significant increase in acetyl-CoA, which impaired the regulation of fatty acid oxidation and glucose metabolism. The latter manifested itself in the muscle-specific PanK4 knockout mice during training by reduced glucose uptake during insulin stimulation and muscle contraction.
In contrast, mice with overexpression of PanK4 showed a significant improvement in glucose uptake in the muscles and a reduction in acetyl-CoA levels, which underlines the importance of PanK4 as a regulator of glucose metabolism. These results suggest that PanK4 plays a key role in the maintenance of metabolic flexibility, particularly with regard to the simultaneous utilization of fatty acids and glucose as energy sources.
New therapeutic approaches
"With PanK4, we have discovered an exciting new protein for muscle metabolism that – due to its importance for metabolism – can compete with established heavyweights such as mTOR, AMPK and Akt," explains Kleinert. "Targeted modulation of PanK4 could help improve metabolic health and support blood sugar control." As a result, PanK4 could be a promising target for therapies to treat metabolic disorders such as type 2 diabetes.
The discovery that PanK4 is activated by exercise and improves energy metabolism in the muscles shows why physical activity is so important for health. "Regular exercise not only ensures increased fitness, but also has a profound effect on the metabolism, which can be a motivating factor for an active lifestyle," says Kleinert.
Role of PanK4 under further investigation
In future studies, Kleinert and his team want to find out how exactly the phosphorylation of PanK4 by exercise or insulin controls its activity and how this is associated with the regulation of acetyl-CoA and metabolic flexibility. The role of PanK4 in other tissues such as the hypothalamus and its effects on systemic energy homeostasis also need further investigation.
