Muscles and nerves are long-lasting, powerful organs whose cellular components are subject to constant wear and tear. The protein BAG3 plays a crucial role in eliminating damaged components, identifying them and ensuring that they are enclosed by cell membranes to form an “autophagosome”. Autophagosomes are like a garbage bag in which cellular waste is collected for later shredding and recycling. The research team led by Professor Jörg Höhfeld from the Institute of Cell Biology at the University of Bonn has shown that strength training activates BAG3 in the muscles. This has important consequences for the removal of cellular waste, because BAG3 must be activated to efficiently bind damaged cell components and promote membrane envelopment. An active elimination or clean-up system is essential for the long-term maintenance of muscle tissue. “Indeed, impairment of the BAG3 system causes rapidly progressive muscle weakness in children and heart failure — one of the most common causes of death in industrialized Western countries,” explains Professor Höhfeld.

Important implications for sports training and physical therapy

The study was conducted with significant involvement from sports physiologists from the German Sports University of Cologne and the University of Hildesheim. Professor Sebastian Gehlert from Hildesheim emphasizes the importance of the findings: “We now know which intensity level of strength training is required to activate the BAG3 system, so that we can optimize training programs for top athletes and help physiotherapy patients to build muscle better.” Professor Gehlert is also using these findings to support members of the German Olympic team.

Essential for the muscles… and more

The BAG3 system is not only active in muscles. Mutations in BAG3 can lead to a nerve disease known as Charcot-Marie-Tooth syndrome (named after its discoverer). The disease causes nerve fibers in the arms and legs to die, leaving the individual unable to move their hands or feet. By studying cells from patients, the research team has now shown that certain manifestations of the syndrome cause faulty regulation of BAG3 elimination processes. The findings demonstrate the far-reaching significance of this system for tissue preservation.

Unexpected regulation points the way to new therapies

When they took a closer look at BAG3 activation, the researchers were surprised by what they saw. “Many cell proteins are activated by the attachment of phosphate groups in a process known as phosphorylation. In BAG3, however, the process is reversed,” explains Professor Jörg Höhfeld, also a member of the Transdisciplinary Research Area (TRA) Life and Health at the University of Bonn, “BAG3 is phosphorylated in resting muscle and the phosphate groups are removed during activation.” At this point, phosphatases become the main focus – the enzymes that remove the phosphate groups. To identify the phosphatases that activate BAG3, Höhfeld is collaborating with chemist and cell biologist Professor Maja Köhn from the University of Freiburg. “Identifying the phosphatases involved is an important step,” she says, “so that we can pursue the development of substances that could potentially influence BAG3 activation in the body.” The research could open up new therapeutic possibilities for muscle weakness, heart failure and nervous diseases.

Relevant for space travel

Work on the BAG3 system is supported by the Deutsche Forschungsgemeinschaft (German Research Institute) through a research unit headed by Prof. Höhfeld. In addition, Höhfeld receives funding from the German Space Agency, as the research is of interest for manned space missions. Professor Höhfeld points out: “BAG3 is activated under mechanical force. But what happens when there is no mechanical stimulation? For example, in astronauts living in a weightless environment, or in immobilized intensive care patients on ventilators?” In such cases, the lack of mechanical stimulation quickly leads to muscle atrophy, which Höhfeld attributes at least partly to the lack of BAG3 activation. Drugs developed to activate BAG3 could help in such situations, he believes, and so Höhfeld’s team is preparing experiments to be conducted aboard the International Space Station (ISS). BAG3 research could thus in fact help us reach Mars one day.

Institutions involved and funding obtained

Partners of the University of Bonn in this study are the University of Freiburg, the German Sports University, Forschungszentrum Jülich, the University of Antwerp and the University of Hildesheim. The work is co-funded by the German Research Foundation and the German Space Agency, part of the German Aerospace Center.