Nfix Regulates Temporal Progression of Muscle Regeneration through Modulation of Myostatin Expression

• Muscle differentiation is delayed in Nfix-null satellite cells in vitro
• Mice lacking Nfix in satellite cells show delayed regeneration upon injury
• Nfix directly regulates Myostatin expression during regeneration
• In vivo silencing of Myostatin rescues the regeneration deficit in Nfix-null mice

SummaryNfix belongs to a family of four highly conserved proteins that act as transcriptional activators and/or repressors of cellular and viral genes. We previously showed a pivotal role for Nfix in regulating the transcriptional switch from embryonic to fetal myogenesis. Here, we show that Nfix directly represses the Myostatin promoter, thus controlling the proper timing of satellite cell differentiation and muscle regeneration. Nfix-null mice display delayed regeneration after injury, and this deficit is reversed upon in vivo Myostatin silencing. Conditional deletion of Nfix in satellite cells results in a similar delay in regeneration, confirming the functional requirement for Nfix in satellite cells. Moreover, mice lacking Nfix show reduced myofiber cross sectional area and a predominant slow twitching phenotype. These data define a role for Nfix in postnatal skeletal muscle and unveil a mechanism for Myostatin regulation, thus providing insights into the modulation of its complex signaling pathway.

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