title: Angiotensin type 2 receptor signaling in satellite cells potentiates skeletal muscle regeneration.
abstract: Patients with advanced congestive heart failure (CHF) or chronic kidney disease (CKD) often have increased angiotensin II (Ang II) levels and cachexia. Ang II infusion in rodents causes sustained skeletal muscle wasting and decreases muscle regenerative potential through Ang II type 1 receptor (AT1R)-mediated signaling, likely contributing to the development of cachexia in CHF and CKD. However, the potential role of Ang II type 2 receptor (AT2R) signaling in skeletal muscle physiology is unknown. We found that AT2R expression was increased robustly in regenerating skeletal muscle after cardiotoxin (CTX)-induced muscle injury in vivo and differentiating myoblasts in vitro, suggesting that the increase in AT2R played an important role in regulating myoblast differentiation and muscle regeneration. To determine the potential role of AT2R in muscle regeneration, we infused C57BL/6 mice with the AT2R antagonist PD123319 during CTX-induced muscle regeneration. PD123319 reduced the size of regenerating myofibers and expression of the myoblast differentiation markers myogenin and embryonic myosin heavy chain. On the other hand, AT2R agonist CGP42112 infusion potentiated CTX injury-induced myogenin and embryonic myosin heavy chain expression and increased the size of regenerating myofibers. In cultured myoblasts, AT2R knockdown by siRNA suppressed myoblast differentiation marker expression and myoblast differentiation via up-regulation of phospho-ERK1/2, and ERK inhibitor treatment completely blocked the effect of AT2R knockdown. These data indicate that AT2R signaling positively regulates myoblast differentiation and potentiates skeletal muscle regenerative potential, providing a new therapeutic target in wasting disorders such as CHF and CKD.
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, Louisiana 70112.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, Louisiana 70112.
authors.forename: Tashfin S
authors.initials: TS
authors.lastname: Huq
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, Louisiana 70112. Electronic address: pdelafon@tulane.edu.
authors.forename: Patrice
authors.initials: P
authors.lastname: Delafontaine
mesh_terms: D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D015870:Gene Expression; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000378:metabolism*; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000502:physiology*
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D009842:Oligopeptides; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; C060894:CGP 42112A; C073402:PD 123319
keywords: AT2 Receptor; Angiotensin II; Heart Failure; Regeneration; Skeletal Muscle; Stem Cells
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