Bonn, August, 23th, 2024. In our body, the disposal of damaged cell components is essential for the maintenance of tissues and organs. An international research team led by the University of Bonn has now gained significant insights into the regulation of one of the disposal systems involved. According to the findings, this system is activated by strength training. The findings could form the basis for new therapies against heart failure and nerve diseases and also contribute to the success of manned space missions. The results are presented in the current issue of the scientific journal „Current Biology“.

Muscles and nerves are long-lived high-performance organs whose cellular components are subject to constant wear and tear. The protein BAG3 plays a decisive role in the disposal of damaged components. It recognises damaged components and ensures that they are enclosed by cellular membranes: A so-called autophagosome is formed. The cellular waste is collected in this „rubbish bag“ and finally shredded for recycling. The research team led by Prof Dr Jörg Höhfeld from the Institute of Cell Biology at the University of Bonn has now shown that BAG3 is activated in the muscles by strength training. This is important for cellular waste disposal, because: Only activated BAG3 efficiently binds damaged cell components and drives membrane envelopment. An active waste disposal system, in turn, is essential for maintaining the muscles in the long term. „Impairment of the BAG3 system does indeed lead to rapidly progressive muscle weakness in children and to heart failure, one of the most common causes of death in western industrialised nations,“ explains Prof. Höhfeld.

Important findings for training and rehabilitation

Sports physiologists from the German Sport University Cologne and the University of Hildesheim played a key role in the study. Professor Sebastian Gehlert from Hildesheim emphasises the importance of the findings: „We now know what training intensity is necessary to activate the BAG3 system. This helps us to optimise training programmes for top athletes and improve muscle building in patients during rehabilitation.“ Gehlert also uses these findings to support members of the German Olympic team.

Not only necessary in muscles

But the BAG3 system is not only active in the muscles. Mutations in BAG3 can also lead to a nerve disease known as Charcot-Marie-Tooth syndrome after its discoverers. This leads to the death of nerve fibres in the arms and legs. As a result, those affected can no longer move their hands and feet. Using cells taken from patients, the research team has now shown that certain forms of the syndrome result in defective regulation of the BAG3 disposal system. The findings thus demonstrate the far-reaching importance of the system for tissue maintenance.

Unexpected regulation points the way for therapies

The researchers were in for a surprise when they analysed the activation of BAG3 in more detail. „Many proteins are activated in the cell by the attachment of phosphate groups, known as phosphorylation. With BAG3, however, the process is reversed,“ says Jörg Höhfeld, who is also a member of the Transdisciplinary Research Area (TRA) “Life and Health” at the University of Bonn. „In resting muscles, BAG3 is phosphorylated and the phosphate groups are removed during activation.“ This puts the phosphatases – enzymes that remove the phosphate groups – at the centre of interest. Höhfeld is collaborating with chemist and cell biologist Prof Maja Köhn from the University of Freiburg to identify the phosphatases that activate BAG3. „Identifying the phosphatases involved is an important step,“ explains Köhn. „It will then allow us to develop active substances that could influence the activation of BAG3 in the body.“ This could open up new possibilities for the treatment of muscle weakness, heart failure and nerve diseases.

Also important for space travel

The German Research Foundation is supporting the work on the BAG3 system as part of a research group headed by Prof Höhfeld. Höhfeld is also receiving funding from the Space Agency at the German Aerospace Centre: „BAG3 is activated by mechanical force. But what happens if the mechanical stimulation fails to materialise? For example, in astronauts in weightlessness or in immobilised and ventilated intensive care patients?“ explains Höhfeld. In these cases, the lack of mechanical stimulation leads to a rapid loss of muscle tone. Höhfeld assumes that the lack of activation of BAG3 drives the muscle loss. Drugs could also be helpful in these cases to activate BAG3. To clarify this, Höhfeld’s team is preparing experiments on board the International Space Station (ISS), among other things. The research on BAG3 could therefore one day contribute to reaching Mars.

Funding and participating institutions

In addition to the University of Bonn, the University of Freiburg, the German Sport University, the Jülich Research Centre, the University of Antwerp and the University of Hildesheim are involved in the study. It was funded by the German Research Foundation and the Space Agency at the German Aerospace Centre.

The text was translated with the support of DeepL Translator, a translation with artificial intelligence

Originalpublikation:

Ottensmeyer, et al.: Force-induced dephosphorylation activates the cochaperone BAG3 to coordinate protein homeostasis and membrane traffic. „Current Biology“, DOI: 10.1016/j.cub.2024.07.088; https://doi.org/10.1016/j.cub.2024.07.088