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Physical activity is not only important for fitness but also for overall health. This is confirmed by a new study conducted under the leadership of Prof. Dr. Maximilian Kleinert at the German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE). His team identified PanK4 as a key regulator of energy metabolism in skeletal muscle, regulating glucose uptake and fatty acid oxidation and being activated by physical exercise. The study suggests that PanK4 could be a promising approach for treating metabolic disorders such as type 2 diabetes. The findings were published in the journal Nature Communications.
Skeletal muscle accounts for 30 to 40 percent of body weight and is critical for maintaining healthy glucose and lipid metabolism. Impairment in the skeletal muscle's capacity to efficiently use or store glucose can disturb overall glucose homeostasis, potentially resulting in insulin resistance – a major risk factor for type 2 diabetes. Nevertheless, there are only a few therapeutic options that target musculature to treat metabolic disorders.
Studies in Humans and Mice
Physical activity enhances glucose uptake in muscles and promotes metabolic flexibility. Therefore, it is an effective method for improving glucose metabolism, particularly in insulin resistance and type 2 diabetes. However, the underlying molecular mechanisms are largely unknown. These mechanisms were the focus of investigations by a broad international research team, including scientists from the German Center for Diabetes Research (DZD), coordinated by Prof. Dr. Maximilian Kleinert, head of the Department of Molecular Physiology of Exercise and Nutrition at the DIfE. Using modern mass spectrometric methods, the team successfully identified proteins that are phosphorylated in human and animal muscles following physical exercise. One of these proteins is pantothenate kinase 4 (PanK4).
To elucidate the role of PanK4 in regulating energy metabolism in skeletal muscle, Kleinert and his team utilized various genetic mouse models (knockout and overexpression) to conduct comprehensive physiological investigations. These studies included treadmill running experiments and glucose tolerance tests to assess metabolic function. Furthermore, the researchers analyzed human muscle tissue samples obtained post-exercise, conducted metabolic analyses, and utilized advanced molecular biological techniques such as RNA sequencing and protein analyses.
Mice Lacking PanK4 are Struggling
The researchers observed that the general absence of PanK4 in mice resulted in reduced growth and decreased skeletal muscle mass, among other effects. Furthermore, animals with a muscle-specific deficiency of PanK4 exhibited an increased fat content and impaired fatty acid oxidation within the muscle tissue. Metabolomic analyses indicated that PanK4 plays a critical role in regulating acetyl-CoA levels in skeletal muscle. The absence of PanK4 led to a significant increase in acetyl-CoA, which disrupted the regulation of fatty acid oxidation and glucose metabolism. During training studies with mice specifically lacking PanK4 in their muscles, this was manifested 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, underscoring the importance of PanK4 as a regulator of glucose metabolism. These results suggest that PanK4 plays a key role in maintaining metabolic flexibility, particularly in terms of the simultaneous utilization of fatty acids and glucose as energy sources.
Novel Therapeutical Approaches
Identifying PanK4 as a key regulator of muscle metabolism offers a promising new avenue for therapeutic interventions. According to Kleinert, "PanK4's significance in metabolism places it alongside established key players like mTOR, AMPK, and Akt. Targeted modulation of PanK4 could potentially improve metabolic health and support blood sugar control, making it a promising target for therapies aimed at treating metabolic disorders such as type 2 diabetes."
Furthermore, the finding that PanK4 is activated by physical activity and enhances energy metabolism in muscles underscores the importance of regular exercise for overall health. Kleinert emphasizes, "Regular physical activity not only enhances fitness but also has profound effects on metabolism, which can serve as a motivating factor for adopting an active lifestyle."
Role of PanK4 to be Further Investigated
Kleinert and his team plan to conduct further investigations to understand the precise mechanisms by which the phosphorylation of PanK4 by exercise or insulin modulates its activity. Specifically, they aim to elucidate how this phosphorylation event influences the regulation of acetyl-CoA levels and metabolic flexibility in skeletal muscle. Moreover, the role of PanK4 in other tissues, including the hypothalamus, and its impact on systemic energy homeostasis will be explored in greater detail.
Prof. Dr. Maximilian Kleinert
Head of the Department of Molecular Physiology of Exercise and Nutrition
phone: 033200 88-2385
e-mail: maximilian.kleinert@dife.de
Miranda-Cervantes, A., Fritzen, A. M., Raun, S. H., Hodek, O., Møller, L. L. V., Johann, K., Deisen, L., Gregorevic, P., Gudiksen, A., Artati, A., Adamski, J., Andersen, N. R., Sigvardsen, C. M., Carl, C. S., Voldstedlund, C. T., Kjøbsted, R., Hauck, S. M., Schjerling, P., Jensen, T. E., Cebrian-Serrano, A., Jähnert, M., Gottmann, P., Burtscher, I., Lickert, H., Pilegaard, H., Schürmann, A., Tschöp, M. H., Moritz, T., Müller, T. D., Sylow, L., Kiens, B., Richter, E. A., Kleinert, M.: Pantothenate kinase 4 controls skeletal muscle substrate metabolism. Nat. Commun. 16(1):345 (2025). [Open Access]
https://doi.org/10.1038/s41467-024-55036-w
Prof. Dr. Maximilian Kleinert, head of the Department of Molecular Physiology of Exercise and Nutrit ...
David Ausserhofer
DIfE
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Prof. Dr. Maximilian Kleinert, head of the Department of Molecular Physiology of Exercise and Nutrit ...
David Ausserhofer
DIfE
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