Altered skeletal muscle function is associated with the pathogenesis of metabolic diseases such as type 2 diabetes. The classIIa histone deacetylases (HDACs), which are chromatin remodelling enzymes, are increased in diabetic muscle and over-expression of these enzymes phenocopies aspects of diabetic muscle (McGee et al., unpublished data). Therefore, we investigated HDAC inhibitors (HDIs) as a novel therapeutic intervention for Type 2 diabetes. 

Broad spectrum HDIs (Scriptaid, TSA) were analysed for their acute effects on metabolic and mitochondrial gene expression, in L6 myotubes. Scriptaid increased the expression of metabolic and mitochondrial genes such as CPT-1α, HSL, tFAM, PGC-1 α, ATP-5d in a time dependent manner, while TSA had little effect (*p< 0.05 vehicle vs Scriptaid). We next examined the effect of Scriptaid on tissue specific histone (H3) acetylation in vivo, following a single IP injection of either 1, 3 or 10mg/kg Scriptaid in mice. Scriptaid increased H3 acetylation largely in soleus and extensor digitorum longus muscle compared with other tissues at the lowest dose. We next studied whether Scriptaid could improve metabolic homeostasis in diet-induced obesity. Eight-week old C57BL6 mice were fed with standard or high fat diet (45% fat) for 12 weeks. In the last 3 weeks, mice received daily injections of Scriptaid (1mg/kg) or vehicle. Scriptaid increased food intake and body weight in both the diet groups (*p< 0.05 veh vs Scriptaid). Scriptaid increased muscle glucose uptake assessed ex vivo, but had no effect on glucose tolerance in either diet group and decreased insulin tolerance in high fat diet animals (^#p < 0.01,HFD(Scr) vs HF(veh).

These studies show that broad spectrum HDIs can improve some muscle metabolic parameters, but reduced whole body insulin action. We are currently examining the efficacy of classIIa specific HDAC inhibition to minimise non-muscle effects on metabolism, as a potential therapeutic strategy for metabolic diseases.