Angiotensin II type 2 receptor regulates skeletal myoblast differentiation: implications for treatment of cachexia and skeletal muscle wasting (1102.34)

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 robustly increased 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 AT2R antagonist PD123319 (PD, 30 mg/kg/d) during CTX‐induced muscle regeneration. PD reduced the size of regenerating myofibers (727.5±54.6 and 516.0±37.0 µm2 in sham and PD, respectively, p<0.05) and the myoblast differentiation marker myogenin and eMyHC expression (56.9% and 40.2% decrease in PD, respectively. p<0.01). In cultured myoblasts, AT2R knockdown by siRNA suppressed myogenin expression and myoblast differentiation via upregulation of phospho‐ERK, and ERK inhibitor U0126 treatment completely blocked the effect of AT2R knockdown. On the other hand, AT2R agonist CGP42112 (CGP, 1 µg/kg/min) infusion in C57BL/6 mice potentiated CTX injury‐induced myogenin and eMyHC expression (44.5% and 79.1% increase in CGP, respectively, p<0.05) and increased the size of regenerating myofibers (784.3±32.1 and 981.1±65.2 µm2 in sham and CGP, respectively. p<0.05). 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.Grant Funding Source: Supported by NIH/NHLBI (R01HL080682 and R01HL070241) and NIH/NIGMS (P20GM103629).