Uncovering key determinants of skeletal muscle repair

Abstract

Skeletal muscle regeneration is a complex process that allows damaged muscle tissue to be repaired and restored to its original function. This process involves a series of coordinated events, including inflammation, satellite cell activation and proliferation, myoblast differentiation and fusion, and muscle fiber maturation. The success of muscle regeneration relies on the ability of satellite cells to differentiate into functional myoblasts, which can fuse with existing fibers or form new fibers to replace damaged or lost muscle tissue. Various factors, such as age, disease, and injury, can impair muscle regeneration, leading to muscle wasting and weakness. Understanding the cellular and molecular mechanisms underlying skeletal muscle regeneration is crucial for developing effective therapeutic strategies to enhance muscle repair and function in various pathologies. In this thesis I sought to understand this regenerative process further by interrogating the earliest cell autonomous mechanisms that transition a muscle stem cell from quiescence to activation. Specifically, I describe Fos, a member of the AP-I family of transcription factors and a classical oncogene, as an early regulator of satellite cell activity which initiates key stem cell functions, including cell cycle entry, proliferative expansion, and muscle regeneration, via induction of ‘‘pro-regenerative’’ target genes that stimulate cell migration, division, and differentiation.Alongside the earliest cell autonomous regulators, I sought to identify cell non autonomous factors that may be directing and aiding the regenerative process via the coordinated effort of muscle resident cell types. To this end, I identified the soluble receptor for advanced glycation end products (sRAGE) as a soluble factor that potentiates context dependent accelerations in skeletal muscle repair post injury.Together, this work provides a more robust understanding of the cell autonomous and non-autonomous mechanisms that direct the complex process of muscle repair and regeneration.