We have previously found that the class IIa histone deacetylases (HDACs) are increased in the muscle of diabetic mice and are increased in response to nutrient overload in muscle cells. Over expression of the class IIa HDACs in muscle cells results in repression of metabolic genes, impaired mitochondrial function, lipid accumulation and insulin resistance (Martin et al., unpublished data). In an effort to gain a functional understanding of why the class IIa HDACs are increased in response to nutrient overload, we performed comparative microarray analyses on diabetic muscle and C2C12 myoblasts overexpressing HDAC4 and 5. Gene set enrichment analysis of co-regulated genes revealed the p53 pathway as the most significantly regulated pathway from these two data sets. Expression profiling of p53 dependent genes in C2C12 myoblasts over expressing HDAC4 and 5 showed that pro-apoptotic genes were decreased, while there was no change in anti-apoptotic genes. To determine the functional consequence of reduced pro-apoptotic gene expression, we exposed cells overexpressing HDAC4 and 5 and control cells to increasing concentrations of glucose, palmitate or TNFα. We observed a dose dependent increase in non-viable cells upon glucose, palmitate and TNFα exposure in control cells, which was significantly suppressed in cells overexpressing HDAC4 and 5. These data suggest that increases in HDAC4 and 5 in response to nutrient overload occur to preserve muscle cell survival and could give insights into the functional consequences of metabolic remodelling of muscle in diseases such as obesity and type 2 diabetes.