Abstract 13071: Angiotensin II Inhibits Satellite Cell Proliferation and Prevents Skeletal Muscle Regeneration
In addition to regulating blood pressure and salt and water balance, the renin-angiotensin system plays an important role in the pathogenesis of cardiovascular and cerebrovascular disease, congestive heart failure (CHF), and chronic kidney disease (CKD). Patients with advanced CHF or CKD often have increased angiotensin II (Ang II) levels, cachexia and skeletal muscle wasting. We have shown that Ang II infusion in rodents causes sustained skeletal muscle wasting. To determine potential effects of Ang II on muscle regeneration, we infused C57BL/6 mice with 1.5 μg/kg/min Ang II to analyze its effect on regeneration after cardiotoxin (CTX)-induced muscle injury. Ang II reduced the number of regenerating myofibers compared to control (71.9% decrease at day 5, p<0.001), and quantitative RT-PCR of gastrocnemius muscle showed reduced expression of satellite cell (SC) proliferation/differentiation markers MyoD and myogenin (56.5% and 62.5% decrease, respectively, p<0.001). SC number was quantified in vivo using Myf5nLacZ/+ mice, in which SCs express β-galactosidase (β-gal), and using muscle stem cell markers CD45-/Sca-1-/CD11b-/CD31-/CD34+/Integrin α7+. Ang II reduced SC number (39.4 % and 16.7% reduction in β-gal positivity in Myf5nLacZ/+ mice and in cell surface markers at 7 days, respectively, p<0.01), and this decrease was blocked by candesartan and in AT1a receptor null mice. Quantitative RT-PCR on isolated SCs, FACS analysis and immunohistochemical staining showed high expression of AT1R in SCs compared to myofibers or interstitial cells, suggesting that Ang II directly acts on SCs to prevent their function. Ang II suppressed MyoD and active-Notch expression in SCs both in vivo and in vitro, and inhibited SC proliferation in vitro. In mice that developed CHF 12 weeks following left anterior descending artery ligation there was high circulating Ang II, skeletal muscle wasting and reduced SC number. These data show that Ang II signals via the AT1aR on SCs and prevents SC proliferation by suppressing MyoD and Notch signaling, thereby inhibiting normal skeletal muscle regeneration. Ang II-mediated inhibition of skeletal muscle regeneration is likely a critical mechanism that plays a major role in muscle wasting in chronic diseases such as CHF and CKD.
- © 2012 by American Heart Association, Inc.