Gene regulation in gastrocnemius muscle of denervated mouse with HDAC4 inducible knockout or class IIa HDAC inhibitior NVS-HD1 treatment

Our class IIa HDAC inhibitor, NVS-HD1, inhibited HDAC4 with less than 1 nM potency while exhibiting >200 fold selectivity on class IIa HDACs compared to class I (HDAC1, 3, 8) and class IIb (HDAC6) HDACs, making it the most potent and selective class IIa HDAC inhibitor reported so far. We tested the efficacy of NVS-HD1 in the mouse denervation model, either alone or on the genetic background of HDAC4 whole-body inducible knockout (HDAC4 iRKO). Global gene expression changes in gastrocnemius muscles were profiled by RNAseq. In the innervated control legs, HDAC4 knockout or NVS-HD1 caused little changes in gene expression compared to WT mice. HDAC4 knockout or NVS-HD1 mainly reversed denervation induced changes and the genes regulated by them largely overlap, suggesting that NVS-HD1 is quite specific against class IIa HDACs. Overall design: Transcriptional profiling was performed in gastrocnemius muscles of female WT and HDAC4 iRKO mice treated with vehicle (VEH) or NVS-HD1. Six-month old mice were subjected to denervation surgery on the left leg. On the same day of surgery, animals were dosed of VEH or 10 mg/kg NVS-HD1 twice daily for two weeks. GAS muscles from innervated control legs (CON) and denervated legs (DEN) were harvested and processed for RNA-seq analysis.