Ricerc@Sapienza

Skeletal muscle regeneration allows the repair of damage resulting from exercise, injury or degenerative diseases. This process depends on satellite cells, adult stem cells that remain quiescent until their function is required for repair. The activation of satellite cells involves their exit from quiescence followed by proliferation and differentiation into myofibers. Many questions remain unanswered, especially with regard to transcription and epigenetic regulation of this process. We have previously reported that Poly(ADP-ribose) Polymerase-1 (PARP-1), a regulator of chromatin function, is rapidly activated upon mitogen stimulation of quiescent fibroblasts and lymphocytes and that the enzyme activity is required for cell cycle re-entry. Preliminary results we obtained in an in vitro cell system that mimics the function of muscle satellite cells, strongly suggest that PARP-1 activity is required for the exit from quiescence also in the muscle system. In light of the enzyme ability to affect chromatin at a global level we hypothesize that PARP-1 may play an important role in switching the transcriptional program from quiescent to activated cells. Considering the possible involvement of PARP-1 in such a critical step of muscle regeneration, we plan to investigate this issue in more depth.
We propose to pursue the following specific objectives:
-provide conclusive evidence that PARP-1 and its activity are required for the function of muscle reserve cells, a faithful in vitro model of satellite cells, and in particular for the G0-G1 transition of the cell cycle and for their myogenic commitment.
-identify the wide range transcriptional targets of PARP-1 during reserve cell activation and the effects of the enzyme activity on chromatin organization.
This basic research will lay the foundations for identifying novel therapeutic targets and for developing effective therapeutic strategies aimed at improving the regenerative potential of satellite cells.