USP7‐dependent control of myogenin stability is required for terminal differentiation in skeletal muscle progenitors

Abstract

Satellite cells (SCs) are myogenic progenitors responsible for skeletal muscle regeneration and maintenance. Upon activation, SCs enter a phase of robust proliferation followed by terminal differentiation. Underlying this myogenic progression, the sequential expression of muscle regulatory transcription factors (MRFs) and the downregulation of transcription factor paired box gene 7 (Pax7) are key steps regulating SC fate. In addition to transcriptional regulation, post-translational control of Pax7 and the MRFs provides another layer of spatiotemporal control to the myogenic process. In this context, previous work showed that Pax7 is ubiquitinated by the E3 ligase neural precursor cell-expressed developmentally downregulated protein 4 and interacts with several proteins related to the ubiquitinproteasome system, including the deubiquitinase ubiquitin-specific protease 7 (USP7). Although USP7 functions in diverse cellular contexts, its role(s) during myogenesis remains poorly explored. Here, we show that USP7 is transiently expressed in adult muscle progenitors, correlating with the onset of myogenin expression, while it is downregulated in newly formed myotubes/myofibers. Acute inhibition of USP7 activity upon muscle injury results in persistent expression of early regeneration markers and a significant reduction in the diameter of regenerating myofibers. At the molecular level, USP7 downregulation or pharmacological inhibition impairs muscle differentiation by affecting myogenin stability. Co-immunoprecipitation and in vitro activity assays indicate that myogenin is a novel USP7 target for deubiquitination. These results suggest that USP7 regulates SC myogenic progression by enhancing myogenin stability.

TGF-β-driven downregulation of the transcription factor TCF7L2 affects Wnt/β-catenin signaling in PDGFRα+ fibroblasts

“…Finally, because our BioGRID analysis suggested the interaction of TCF7L2 with deubiquitinating enzymes (e.g. USP4), we evaluated the amount of TCF7L2 protein in C3H/10T1/2 MSCs treated with the ubiquitin-specific protease 7 (USP7) inhibitor HBX 41108 (HBX) in proliferating conditions (Colland et al, 2009;de la Vega et al, 2020;Yuan et al, 2018). Treatment with only HBX diminished TCF7L2 protein levels in a time-dependent manner (Fig.…”

Mechanisms of skeletal muscle repair and regeneration in health and disease

“…injuries triggering acute muscle regeneration in animal models. An example is shown by de la Vega et al [5], who report that important components of the ubiquitin proteasome system are necessary for activation of the myogenic transcriptional programme after myofiber cytotoxic injury. Some of the satellite cells in muscle may also continue to contribute to continued normal postnatal growth and muscle maintenance.…”

The Gentle Side of the UPS: Ubiquitin-Proteasome System and the Regulation of the Myogenic Program

“…A pro-myogenic effect of DUB activity was recently reported by De la Vega and cols. ( de la Vega et al, 2020 ). The authors showed that Myogenin was deubiquitinated by USP7, favoring Myogenin accumulation in differentiating cells.…”