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.
Highlights
Angiotensin II induces skeletal muscle atrophy, but the function of other renin-angiotensin system components in skeletal muscle physiology is understood poorly
These data suggest that Angiotensin II type 2 receptor (AT2R) expression is induced during the process of satellite cell differentiation. Consistent with these data, AT2R mRNA and protein expression was highly up-regulated in primary satellite cells and C2C12 myoblasts after cells were induced to differentiate (Fig. 1, B and C). These data strongly suggest that up-regulation of AT2R expression during satellite cell differentiation may play an important role in muscle regenerative processes
renin-angiotensin system (RAS) components such as angiotensinogen and angiotensin-converting enzyme are expressed in the skeletal muscle microcirculation [32] and in myoblasts [33], there have been limited data on the biological effects of angiotensin II (Ang II) or other components of the RAS on skeletal muscle
Summary
Angiotensin II induces skeletal muscle atrophy, but the function of other renin-angiotensin system components in skeletal muscle physiology is understood poorly. 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. 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. Angiotensin-converting enzyme inhibitor treatment improves weight loss in CHF patients [14], and Ang II type 1 receptor (AT1R) blockade prevents skeletal muscle atrophy in a rat model of CHF [17], suggesting that Ang II could play an important role in the development of cachexia and that the RAS could represent a common mechanism regulating skeletal muscle function in chronic diseases. Our findings indicate that AT2R expression is increased dramatically in satellite cells during differentiation and that the AT2R is a critical positive regulator of myoblast differentiation and skeletal muscle regenerative processes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
