Sunday, May 11, 2025
5/11/2025
Promotion of satellite cell proliferation by cAMP signaling - SUMMARY Skeletal muscle regeneration requires activation and proliferation of a resident population of stem cells known as satellite cells. Satellite cells are not only required for muscle regeneration after injury but are also thought to contribute to ongoing maintenance of muscle mass. Unfortunately, the number and activity of these progenitors declines with aging and muscular dystrophy. Therefore, pharmacologic strategies to promote expansion of myogenic satellite cells could potentially be used to improve muscle regeneration and preserve muscle function in individuals with muscle disease or individuals of advanced age. Signaling through the cAMP pathway stimulates myogenic progenitor cell proliferation during embryonic development and is sufficient to stimulate proliferation of these cells in vitro. This pathway is also activated during regeneration in adult mice. However, it is unknown whether cAMP signaling in myogenic progenitor cells in response to injury is sufficient to enhance proliferation in vivo. We previously showed that the cAMP-responsive transcription factor CREB is activated in areas of proliferation after acute muscle injury in mice and that mice expressing an activated mutant of CREB have enhanced myoblast proliferation after injury. This project employs biochemical and chemical-genetic tools to determine whether chemical-genetic elevation and genetic regulation of cAMP signaling specifically in satellite cells alters proliferation and muscle regeneration in vivo through regulation of CREB/CRTC transcriptional complexes. We will interrogate the regulation and function of cAMP-regulated CREB co-activators (CRTCs) in satellite cell proliferation and use unbiased transcriptomic approaches to identify CREB/CRTC target genes that contribute to the cAMP-driven proliferative response. We will undertake mechanistic studies to characterize molecular regulation of CRTCs and the mechanism of CRTC recruitment to cAMP-regulated genes in proliferating satellite cells. Results of this project will yield insights into fundamental mechanisms that drive satellite cell proliferation and expansion. The long-term goal is to identify new pharmacologic targets to improve muscle regeneration and function in patients with muscle disease and age-related sarcopenia.
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