Activin type II receptor signaling in cardiac aging and heart failure

Abstract

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.

ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia

“…In support of this observation, others have recently demonstrated that the myostatin/ACVR2B signalling is up-regulated in the heart of patients with heart failure 75 and that targeting ACVR2B can improve cardiac function in models of ageing, ischaemia, and myocardial infarction, thereby implicating activin signalling as a negative input on cardiac function. [76][77][78] To our knowledge, ours is the first report providing evidence that ACVR2B could represent a potent therapeutic target to preserve cardiac function in the occurrence of metastatic CRC. Interestingly, cardiac function is preserved despite no effects in terms of whole-heart size, LV mass, nor major impact on regulators of muscle growth, thereby suggesting that signalling through ACVR2B is not critical in regulating heart size in metastatic CRC.…”

Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice

“…Lastly, it is important to note that our RNAseq analyses did not identify significant transcriptional changes in targets that have been previously reported in ExT aged rodents, such as SERCA2a, VEGF, and SIRT1 (Lai et al., 2014; Lemitsu et al, 2006; Tate et al., 1996). However, it is likely that some of these targets, such as SERCA2a, are largely regulated at a post‐transcriptional level in the aged heart (Roh et al., 2019).…”

Similar sequences but dissimilar biological functions of GDF11 and myostatin

“…Zhou et al 73 also observed that injection of recombinant GDF11 protein into older rats significantly hindered muscle regeneration and function and induced tissue fibrosis. In addition, several other recent studies have shown that exogenous GDF11 treatment inhibits muscle growth 74,75 and reduces strength 76 , while overexpression of the GDF11 propeptide, which antagonizes both mature GDF11 and MSTN, exerts beneficial effects 23,77 .…”