Poster abstracts
Poster number 99 submitted by Kristina Sattler
Med12 inactivation in myogenic progenitors impairs skeletal muscle differentiation
Kristina M. Sattler (Molecular, Cellular, and Developmental Biology Graduate Program), Kedryn K. Baskin (Department of Physiology and Cell Biology, The Ohio State University), Christoph Lepper (Department of Physiology and Cell Biology, The Ohio State University)
Abstract:
Skeletal muscle holds a striking capacity for injury regeneration; the source of which derives from skeletal muscle stem cells, or satellite cells (SCs), which reside in quiescence during tissue homeostasis. SCs readily activate and proliferate in response to acute injury, followed by elongation and fusion into multinucleated myotube syncytia, which then continue to mature into contractile myofibers. This stepwise transition through the myogenic lineage requires precise transcriptional programs directed by the Myogenic Regulatory Factors, a series of stage-specific transcription factors; yet coordination of these transcriptional programs is obscure. The Mediator Complex is comprised of 26-30 protein subunits in mammals, divided into four submodules: Head, Middle, Tail, and Kinase. The Kinase Submodule consists of MED12, MED13, CyclinC, and CDK8, and reversibly interacts with Core Mediator and the preinitiation complex to modulate transcription. In cardiomyocytes and hematopoietic stem cells, MED12 has been shown to carry tissue-specific roles for coordinating transcriptional programs; however, whether MED12 plays a comparable role in SCs is unknown. We hypothesize that MED12 is necessary for coordinating the complex transcriptional programs to progress through regenerative myogenesis. To investigate the role of MED12 in SCs, we genetically inactivated Med12 specifically in adult SCs and assayed for SC maintenance and regenerative capacity. The Med12-deficient SC pool is reduced, and SCs abnormally break quiescence to produce new fibers independent of injury. Following injury, early fiber formation is delayed and regenerated fibers remain small and persistently express embryonic myosin >21 days post-injury. Further, Med12-deficient SCs exhibit severe proliferation and fusion defects in vitro. From these data, we conclude that MED12 is crucial for orchestrating transcriptional programs that control SC quiescence, proliferation, fusion, and terminal differentiation.
Keywords: skeletal muscle stem cells, regenerative myogenesis, transcription