Promotion Of Muscle Satellite Cell Proliferation By cAMP‐Induced Transcription

Abstract

The cAMP‐activated transcription factor CREB stimulates proliferation of myogenic progenitor cells during embryonic development, and genetic activation of CREB stimulates proliferation during muscle regeneration. Proliferation of muscle progenitor cells, known as satellite cells, declines during aging. We hypothesized that pharmacologic activation of the cAMP‐CREB pathway would promote satellite cell proliferation after injury and that cAMP‐regulated CREB co‐activators (CRTCs) contribute to CREB‐regulated target gene expression during satellite cell proliferation. To test this, we created ROSA26‐GsDREADD knock‐in mice for tissue‐specific expression of a Gs‐coupled DREADD (Designer Receptor Exclusively Activated by Designer Drugs, “GsD”). After tamoxifen‐induced expression of GsD in muscle satellite cells in young adult mice, activation of the receptor by the GsD ligand CNO (clozapine N‐oxide) increased proliferation after muscle injury. Consistent with our hypothesis, myoblasts over‐expressing constitutively active CRTC2 had increased cell proliferation in vitro, and Crtc2 knockout mice had reduced proliferation after muscle injury. Our results indicate that cAMP signaling enhances satellite cell proliferation in vivo and cAMP regulated CREB coactivator 2 (CRTC2) contributes to the proliferative response after muscle injury. ROSA26‐GsDREADD mice can therefore be used to stimulate cAMP signaling in specific cell populations in vivo to study the effects of pharmacologic activation of cAMP signaling without using ligands that have pleiotropic effects in other cell types.Support or Funding InformationResearch reported in this abstract was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number R01‐AR059847. DA was supported by a Postdoctoral Fellowship from the American Heart Association (15POST25090134). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.