Abstract 4147508: Targeting Angiotensin II Type 2 Receptor Skeletal Muscle Stem Cells to Prevent Skeletal Muscle Atrophy and Fibrosis in Congestive Heart Failure

Introduction: We have previously shown that angiotensin II (Ang II) type 2 receptor (AT2R) positively regulates skeletal muscle stem cell (MuSC) differentiation. Systemic angiotensin II (Ang II) increase or congestive heart failure (CHF) suppress AT2R expression, likely contributing to the development of skeletal muscle atrophy and fibrosis associated with these conditions. Hypothesis: We hypothesized that AT2R overexpression in MuSCs could prevent skeletal muscle atrophy and fibrosis associated with CHF. Approach: Two mouse models, systemic Ang II infusion and left anterior descending coronary artery (LAD) ligation were used in this study. MuSC differentiation, muscle atrophy and muscle fibrosis were assessed by analyzing gene expressions (e.g. myogenin and atrogin-1), myofiber cross sectional area, and the collagen deposition (Collagen I immunohistochemical staining and picrosirius red staining). Primary MuSCs were isolated from mouse hindlimb muscles. MuSC-specific AT2R-overexpressing transgenic mice were generated by crossing Pax7 CreER/+ mice (tamoxifen-inducible cre recombinase is expressed under Pax7 promoter) and CAG-stop flox -AT2R mice (AT2R is expressed under CMV early enhancer element, chicken β-actin gene promoter upon cre-mediated excision of floxed stop codon). Results: AT2R expression was robustly increased during MuSC differentiation both in vitro and in vivo . In both Ang II infusion and LAD ligation models, AT2R induction in MuSCs was significantly suppressed, associated with reduced muscle regeneration and increased atrophy and fibrosis. Consistently, AT2R knockdown significantly suppressed MuSC differentiation in vitro and skeletal muscle regeneration in vivo , leading to increased skeletal muscle fibrosis. Restoring AT2R levels via MuSC-specific AT2R overexpression in vivo increased muscle regenerative capacity (increased regenerative marker expressions), reduced muscle atrophy (reduced atrophy markers and increased myofiber cross sectional area) and fibrosis (decreased collagen) in CHF models. Conclusions: AT2R induction in MuSC is suppressed in CHF, possibly via increased Ang II. Decreased AT2R expression and its downstream signaling in MuSC lead to lowered muscle regenerative capacity and increased muscle atrophy and fibrosis. AT2R overexpression in MuSCs restores their regenerative potential, and prevent muscle atrophy and fibrosis in CHF condition.