In a new study, University of Illinois professor Jie Chen and collaborators have uncovered novel molecular mechanisms of regulation in skeletal muscle regeneration.

Humans possess over 70 guanine exchange factor (GEF) proteins that are important in intracellular cell signaling. Rho-dependent ARHGEF3 is an activator for a small family of G proteins that act as a molecular switch and are involved in signal transduction. Despite their abundance and fundamental role in signaling, GEF proteins are not often studied in physiological settings. Jie Chen, a professor of cell and developmental biology, and members of her lab are at the forefront of exploring the physiological functions of Rho-GEF.

The Chen lab is the first to explore the effect of ARHGEF3 depletion in mice. Professor Chen and postdoctoral fellow Jae-Sung You, the lead and co-corresponding author, link the deletion of ARHGEF3 with skeletal muscle regeneration in “ARHGEF3 Regulates Skeletal Muscle Regeneration and Strength through Autophagy.” This article was published in Cell Reports early this year.

“The deletion of ARHGEF3 leads us to identify potential therapeutic targets for impaired muscle regeneration among other clinical issues,” making this such a promising and exciting study, Chen said.

ARHGEF3, the primary focus of the study, was previously recognized as a negative regulator of myoblast differentiation in cell culture, where the regulator acts independently of its GEF activity and relies on Akt signaling. In the current study, Chen and colleagues discovered that ARHGEF3 plays a role in skeletal muscle regeneration after studying ARHGEF3-knockout mice, which were created with technologies provided by Huimin Zhao, a professor of chemical and biomolecular engineering at UIUC. They found that while there was no change in phenotype in knockout mice under basal conditions, after acute injury, muscle fiber size and mass were enhanced in young and middle-aged, muscle regeneration-deficient KO mice. To their surprise, the Chen lab found that this phenotype was independent of Akt, and rather occurred via the GEF activity of ARHGEF3.

Through further studies, they found that the knockout of the gene promotes muscle regeneration by activating autophagy, a critical process in muscle regeneration, maintaining muscle strength, and other physiological and pathophysiological conditions including cancer. Not only did the Chen lab’s studies show that deletion of ARHGEF3 enhances autophagy—and therefore muscle regeneration—in young and middle-aged mice, but also that gene knockout could be used as a preventive agent. Preliminary studies done by the lab showed that by restoring autophagy, ARHGEF3 KO prevented muscle weakness in old mice. Additionally, because of the general role of autophagy in many human diseases, targeting ARHGEF3 could have potential implications in therapeutics.

Not only has the Chen lab’s research provided insight into the role of ARHGEF3 on skeletal muscle regeneration, but it has also alluded to the potential role of GEF proteins in more general clinical issues involving autophagy, such as cancer. Chen’s research may have major implications on the future study of GEF proteins. Prior to this study, because of the perceived redundancy in their function, GEF proteins were underexplored in vivo. However, she hopes that her lab’s novel and exciting findings will “encourage researchers to study other Rho-GEFs as well.”

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