Abstract 14845: Angiotensin II Type 2 Receptor Regulates Skeletal Myoblast Differentiation: Implications for Treatment of Cachexia and Skeletal Muscle Wasting
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 was barely detectable in mouse muscle, but after cardiotoxin (CTX)-induced muscle injury AT2R expression was robustly increased in regenerating skeletal muscle. AT2R expression was also not detectable in myoblasts (mouse primary myoblast and C2C12 myoblast cell line) but was markedly upregulated after induction of differentiation 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). Myogenin and eMyHC expression was also reduced by AT2R siRNA electroporation to hindlimb muscles. 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.
- © 2013 by American Heart Association, Inc.