The study investigates the role of histone deacetylases (HDACs) in muscle differentiation, focusing on the signal-dependent nuclear export of HDAC5. HDACs, particularly HDAC4 and HDAC5, repress muscle differentiation by inhibiting the transcription factor MEF2. Calcium/calmodulin-dependent protein kinase (CaMK) signaling, which stimulates myogenesis, disrupts MEF2-HDAC complexes and induces the nuclear export of HDAC4 and HDAC5 through phosphorylation. The study demonstrates that an HDAC5 mutant lacking two CaMK phosphorylation sites is resistant to CaMK-mediated nuclear export and inhibits skeletal myogenesis. Conversely, a cytoplasmic HDAC5 mutant fails to block the muscle differentiation program. The results highlight a mechanism where HDAC5's nuclear export is regulated by CaMK signaling, allowing MEF2 to activate genes essential for muscle development. This mechanism suggests that the nucleocytoplasmic trafficking of HDACs plays a crucial role in controlling cellular differentiation.The study investigates the role of histone deacetylases (HDACs) in muscle differentiation, focusing on the signal-dependent nuclear export of HDAC5. HDACs, particularly HDAC4 and HDAC5, repress muscle differentiation by inhibiting the transcription factor MEF2. Calcium/calmodulin-dependent protein kinase (CaMK) signaling, which stimulates myogenesis, disrupts MEF2-HDAC complexes and induces the nuclear export of HDAC4 and HDAC5 through phosphorylation. The study demonstrates that an HDAC5 mutant lacking two CaMK phosphorylation sites is resistant to CaMK-mediated nuclear export and inhibits skeletal myogenesis. Conversely, a cytoplasmic HDAC5 mutant fails to block the muscle differentiation program. The results highlight a mechanism where HDAC5's nuclear export is regulated by CaMK signaling, allowing MEF2 to activate genes essential for muscle development. This mechanism suggests that the nucleocytoplasmic trafficking of HDACs plays a crucial role in controlling cellular differentiation.