Copper-Dependent Transcriptional Networks in Skeletal Muscle Differentiation & Regeneration

Copper is an essential trace element required for mitochondrial respiration, neurotransmitter synthesis, antioxidant defense, and transcriptional regulation. Disruption of copper homeostasis contributes to pathological conditions affecting neuronal, cognitive, and skeletal muscle development. Although its enzymatic roles are well established, its functions in gene regulation remain incompletely understood. Here, we investigate novel copper-binding proteins during skeletal muscle differentiation using murine primary myoblasts and regeneration models. Metalloproteomics identified distinct nuclear and cytoplasmic copper-binding proteins, suggesting compartment-specific functions. Structural and biochemical analyses indicate that copper binding can compete with other metal cofactors, altering protein stability, conformation, and activity. Functional studies show that these proteins differentially regulate myogenesis by controlling transcriptional programs. Integrative genomics links them to networks governing myogenic transcription factors, cell cycle, chromatin remodeling, and metal-responsive genes. Together, these findings identify copper-binding proteins as regulators of muscle differentiation and support copper as a signaling and transcriptional regulator beyond classical enzymatic roles well.