O‐GlcNAcylation is a widespread nutrient sensitive post‐translational modification that satellite cells (SCs) use to maintain homeostasis and proper SC function. Ablation of SC specific OGT impairs adult regenerative myogenesis, in vivo cycling properties, and proliferation, presumably through an HCF1‐mediated arrest in the cell cycle.
Abstract
O‐GlcNAcylation is a post‐translational modification considered to be a nutrient sensor that reports nutrient scarcity or surplus. Although O‐GlcNAcylation exists in a wide range of cells and/or tissues, its functional role in muscle satellite cells (SCs) remains largely unknown. Using a genetic approach, we ablated O‐GlcNAc transferase (OGT), and thus O‐GlcNAcylation, in SCs. We first evaluated SC function in vivo using a muscle injury model and found that OGT deficient SCs had compromised capacity to repair muscle after an acute injury compared to the wild‐type SCs. By tracing SC cycling rates in vivo using the doxycycline‐inducible H2B‐GFP mouse model, we found that SCs lacking OGT cycled at lower rates and reduced in abundance with time. Additionally, the self‐renewal ability of OGT‐deficient SCs after injury was decreased compared to that of the wild‐type SCs. Moreover, in vivo, in vitro, and ex vivo proliferation assays revealed that SCs lacking OGT were incapable of expanding compared to their wild‐type counterparts, a phenotype that may be explained, at least in part, by an HCF1‐mediated arrest in the cell cycle. Taken together, our findings suggest that O‐GlcNAcylation plays a critical role in the maintenance of SC health and function in normal and injured skeletal muscle.
© AlphaMed Press 2021
Significance Statement
Satellite cells contribute to skeletal muscle health and muscle repair after injury. Satellite cell behavior is governed by nutrient availability, yet the underpinning mechanism remains poorly understood. Herein, we demonstrate that O‐GlcNAcylation is critical for satellite cells to maintain their homeostasis and adjust their behaviors in normal physiological conditions and during adult regenerative myogenesis.