Retinoid-related orphan receptor γ regulates several genes that control metabolism in skeletal muscle cells:: links to modulation of reactive oxygen species production

Retinoid-related orphan receptor gamma (ROR gamma) is an orphan nuclear hormone receptor (NR) that is preferentially expressed in skeletal muscle and several other tissues, including pancreas, thymus, prostate, liver and testis. Surprisingly, the specific role of ROR gamma in skeletal muscle, a peripheral tissue, has not been examined. Muscle is one of the most energy demanding tissues which accounts for similar to 40% of the total body mass and energy expenditure, > 75% of glucose disposal and relies heavily on beta-oxidation of fatty acids. We hypothesize that ROR gamma regulates metabolism in this major mass lean tissue. This hypothesis was examined by gain and loss of function studies in an in vitro mouse skeletal muscle cell culture model. We show that ROR gamma mRNA and protein are dramatically induced during skeletal muscle cell differentiation. We utilize stable ectopic over-expression of VP16-ROR gamma (gain of function), native ROR gamma and ROR gamma Delta H12 (loss of function) vectors to modulate ROR gamma mRNA expression and function. Ectopic VP16 (herpes simplex virus transcriptional activator)-ROR gamma and native ROR gamma expression increases ROR alpha mRNA expression. Candidate-driven expression profiling of lines that ectopically express the native and variant forms of ROR gamma suggested that this orphan NR has a function in regulating the expression of genes that control lipid homeostasis (fatty acid-binding protein 4, CD36 (fatty acid translocase), lipoprotein lipase and uncoupling protein 3), carbohydrate metabolism (GLUT5 (fructose transporter), adiponectin receptor 2 and interleukin 15 (IL-15)) and muscle mass (including myostatin and IL-15). Surprisingly, the investigation revealed a function for ROR gamma in the pathway that regulates production of reactive oxygen species.