Establishing the BAG3 protein homeostasis system as a diagnostic marker and potential therapeutic target for space flight induced muscle loss

Abstract

Muscle dystrophy is a prevalent health issue that astronauts suffer from after returning to Earths gravity. A detailed understanding of cellular mechanisms underlying muscle maintenance will contribute to the development of optimized countermeasures for the prevention of space flight induced muscle loss. Our work over the last couple of years has identified the protein BAG3 as a central component of a protein homeostasis (proteostasis) system, which is essential for maintaining the architecture and function of cardiac and skeletal muscle. In cooperation with molecular chaperones and other interaction partners, BAG3 recognizes mechanically unfolded and damaged cytoskeleton proteins and mediates their disposal through chaperone-assisted selective autophagy (CASA). Moreover, BAG3 stimulates transcription and translation to compensate protein degradation during muscle maintenance. In ESA-CORA-GBF supported work, we showed that the expression of BAG3 and some of its interaction partners in both skeletal as well as smooth muscle cells is sensitive to changes in gravitational load. The obtained data support the hypothesis that micro- and hypergravity result in a deregulation of the BAG3 machinery, which could significantly contribute to muscle loss during space flight. In addition, we observed that the cellular concentrations of BAG3 and the BAG3 interaction partner p62 is significantly increased under simulated microgravity. These findings are consistent with a shut-down of BAG3-mediated degradation in the absence of gravitational load, which would in turn affect muscle maintenance. Apparently, detection of BAG3 and BAG3 partner proteins in muscle biopsies would provide a valuable new measure to evaluate muscle functionality and muscle health in astronauts. Finally, we established growth and differentiation conditions of isolated murine muscle cells, which would allow to extend experimental strategies to real microgravity. Mission-suitable ibidi u-channel slides were used for cultivation under space flight conditions and parameters for channel coating and automated medium exchange by life-support systems were identified. The results provide an important basis for future analysis of the BAG3 muscle maintenance system under real microgravity on board of the ISS or other gravity research platforms.