ChREBP Is Dispensable for Myofiber Type Switch but Promotes Skeletal Muscle Regeneration

Background/Objectives: The transcription factor carbohydrate response element-binding protein (ChREBP) is a key glucose-sensing regulator that governs glucose and lipid metabolic homeostasis. However, its specific functions in skeletal muscle remain insufficiently clarified. The present study aimed to investigate the roles of ChREBP in skeletal muscle exercise capacity, energy metabolism, and adaptive remodeling, as well as muscle regeneration. Methods: We generated a skeletal muscle-specific ChREBP knockout mouse model, and assessed their exercise performance, energy metabolism, skeletal muscle fiber composition, and injury repair capacity. Additionally, hypoxia and high-fructose diet models were established to analyze the function of ChREBP in skeletal muscle adaptive remodeling. C2C12 myoblasts and primary muscle satellite cells were used to explore its effects on myogenic differentiation. Results: Genetic deletion of ChREBP induced no detectable alterations in myofiber composition, overall metabolic status, or muscle adaptive remodeling triggered by hypoxia and high-fructose diet. In vitro assays demonstrated that ChREBP overexpression facilitates C2C12 myogenic differentiation. Adeno-associated virus-mediated ChREBP overexpression enhanced histological markers of regeneration, including desmin-positive regenerative area and the cross-sectional area of newly formed myofibers after cardiotoxin-induced injury. Conclusions: Collectively, our experimental data indicate that ChREBP is largely dispensable for maintaining basal skeletal muscle homeostasis and stress-induced adaptive remodeling. Meanwhile, this study identifies a previously unrecognized regulatory role of ChREBP in the processes of skeletal muscle damage repair and post-injury regeneration.