HDAC5 shuttles between the nucleus and cytoplasm during muscle differentiation, regulated by CaMK signaling. MEF2 transcription factors activate skeletal myogenesis by interacting with MyoD, while HDAC4 and HDAC5 repress MEF2-dependent genes by binding to MEF2. CaMK signaling prevents MEF2-HDAC complexes and promotes HDAC5 nuclear export, which is essential for muscle differentiation. HDAC5 nuclear export is mediated by CaMK phosphorylation, which facilitates its interaction with exportin Crm1. Mutant HDAC5 lacking CaMK phosphorylation sites remains nuclear and inhibits myogenesis, while cytoplasmic HDAC5 mutants fail to block differentiation. HDAC5's nuclear localization is regulated by its N and C termini, with specific sequences controlling nuclear import and export. Phosphorylation of Ser 259 and Ser 498 is critical for HDAC5 nuclear export. HDAC5 nuclear export is required for MEF2 activation and muscle differentiation. CaMK signaling promotes HDAC5 nuclear export, which is essential for myogenesis. HDAC5's nuclear export is involved in regulating cellular differentiation, and its activity is controlled by various signaling pathways, including CaMK, MAP kinases, and calcineurin. HDAC5's nuclear export is a key mechanism for signal-dependent regulation of myogenesis.HDAC5 shuttles between the nucleus and cytoplasm during muscle differentiation, regulated by CaMK signaling. MEF2 transcription factors activate skeletal myogenesis by interacting with MyoD, while HDAC4 and HDAC5 repress MEF2-dependent genes by binding to MEF2. CaMK signaling prevents MEF2-HDAC complexes and promotes HDAC5 nuclear export, which is essential for muscle differentiation. HDAC5 nuclear export is mediated by CaMK phosphorylation, which facilitates its interaction with exportin Crm1. Mutant HDAC5 lacking CaMK phosphorylation sites remains nuclear and inhibits myogenesis, while cytoplasmic HDAC5 mutants fail to block differentiation. HDAC5's nuclear localization is regulated by its N and C termini, with specific sequences controlling nuclear import and export. Phosphorylation of Ser 259 and Ser 498 is critical for HDAC5 nuclear export. HDAC5 nuclear export is required for MEF2 activation and muscle differentiation. CaMK signaling promotes HDAC5 nuclear export, which is essential for myogenesis. HDAC5's nuclear export is involved in regulating cellular differentiation, and its activity is controlled by various signaling pathways, including CaMK, MAP kinases, and calcineurin. HDAC5's nuclear export is a key mechanism for signal-dependent regulation of myogenesis.