LAUSR

Activin type II receptor signaling regulates cardiac function in aging and heart failure by modulating proteasome-dependent SERCA2a degradation. Aging, activins, and heart failure Age is a risk factor for heart failure, but the underlying mechanisms remain unclear. Roh et al. found that circulating follistatin-like 3 and activins, ligands for activin type II receptor (ActRII), were increased with aging and disease severity in human plasma samples from patients with heart failure. Blocking ActRII in mouse models of heart failure preserved cardiac function. ActRII signaling up-regulated the proteasome pathway in cardiomyocytes, leading to degradation of the sarcoplasmic reticulum ATPase pump SERCA2a, which is important for calcium handling and cardiomyocyte function. These results help explain how aging may contribute to heart failure and identify a potential therapeutic target. Activin type II receptor (ActRII) ligands have been implicated in muscle wasting in aging and disease. However, the role of these ligands and ActRII signaling in the heart remains unclear. Here, we investigated this catabolic pathway in human aging and heart failure (HF) using circulating follistatin-like 3 (FSTL3) as a potential indicator of systemic ActRII activity. FSTL3 is a downstream regulator of ActRII signaling, whose expression is up-regulated by the major ActRII ligands, activin A, circulating growth differentiation factor-8 (GDF8), and GDF11. In humans, we found that circulating FSTL3 increased with aging, frailty, and HF severity, correlating with an increase in circulating activins. In mice, increasing circulating activin A increased cardiac ActRII signaling and FSTL3 expression, as well as impaired cardiac function. Conversely, ActRII blockade with either clinical-stage inhibitors or genetic ablation reduced cardiac ActRII signaling while restoring or preserving cardiac function in multiple models of HF induced by aging, sarcomere mutation, or pressure overload. Using unbiased RNA sequencing, we show that activin A, GDF8, and GDF11 all induce a similar pathologic profile associated with up-regulation of the proteasome pathway in mammalian cardiomyocytes. The E3 ubiquitin ligase, Smurf1, was identified as a key downstream effector of activin-mediated ActRII signaling, which increased proteasome-dependent degradation of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), a critical determinant of cardiomyocyte function. Together, our findings suggest that increased activin/ActRII signaling links aging and HF pathobiology and that targeted inhibition of this catabolic pathway holds promise as a therapeutic strategy for multiple forms of HF.