Regulation of Striated Muscle Metabolism and Function by Mediator Complex

Mediator is a multi-protein complex that links signal-dependent transcription factors and upstream regulators with polymerase II (Pol II) to form a stable and efficient pre-initiation complex (PIC). Recent studies have suggested that different compositions of subunits in Mediator in a cell-specific and signal-dependant manner, which permits customizable regulation of different subsets of genes, and variable responses to signals from transcription factors. In this way, Mediator allows for response to the continuous changes of the cellular environment. Our studies have implicated the mediator subunit MED13 in the control of cardiac and skeletal muscle metabolism. MED13, along with MED12, cyclin C and cdc8, form the kinase module of the Mediator complex, which is thought to function as an accessory repressor or activator of Mediator. To investigate the potential role of MED12 in striated muscle functions, we generated mice with conditional deletion of MED12 in the heart and skeletal muscle. Mice with cardiac deletion of MED12 display postnatal cardiomyopathy with dysregulation of genes involved in calcium homeostasis and contractility. Mice with skeletal muscle deletion of MED12 show severe muscle defects and a failure to thrive, which likely reflects a role of this Mediator subunit in the control of muscle growth. Collectively, these highlight distinct roles of the kinase module of the Mediator complex in cardiac and skeletal muscle development and function.