The effect of HDAC inhibitor, 4b, on skeletal muscle gene expression

To assess the effects of histone deacetylase (HDAC) inhibitor, HDACi 4b, treatment on muscle function on a molecular level, we performed microarray analysis on skeletal muscle (gastrocnemius) samples from wt and N17182Q mice treated with the HDAC inhibitor 4b for 3 months (50 mg/kg; s.c. injection 3x weekly; n=4 per group). The transcriptome pattern in N17182Q mice compared to wt controls consisted of deficits in the expression of genes related to mitochondrial function and oxidative metabolism. In addition, we noted that numerous genes associated with basal contractile function were altered in HD N17182Q mice. These include genes related to the muscle contractile complex, Tnnt3 and Myh8, as well as several additional myosin genes: myosin heavy chain genes, Myh10 and Myh4, and myosin light chain genes, Myl1, Mylc2 and Mylk. These findings implicate deficits in the underlying contractile function in skeletal muscle from HD mice. Further, we found robust effects of 4b treatment on the expression of genes in skeletal muscle, with 556 genes showing significantly altered expression, at p<0.005, in 4b-treated N17182Q muscle compared to vehicle-treated control mice. n=4 vehicle-treated WT mice, n=5 HDACi 4b-treated WT mice, n=4 vehicle-treated N17182Q transgenic mice, and n=3 HDACi 4b-treated N17182Q transgenic mice.