Activin type II receptor ligand signaling inhibition after experimental ischemic heart failure attenuates cardiac remodeling and prevents fibrosis

Abstract

Myostatin (MSTN) is a transforming growth factor (TGF)-β superfamily member that acts as a negative regulator of muscle growth and may play a role in cardiac remodeling. We hypothesized that inhibition of activin type II receptors (ACTRII) to reduce MSTN signaling would reduce pathological cardiac remodeling in experimental heart failure (HF). C57BL/6J mice underwent left anterior descending coronary artery ligation under anesthesia to induce myocardial infarction (MI) or no ligation (sham). MI and sham animals were each randomly divided into groups ( n ≥ 10 mice/group) receiving an ACTRII or ACTRII/TGFβ receptor-signaling inhibiting strategy: 1) myo-Fc group (weekly 10 mg/kg Myo-Fc) or 2) Fol + TGFi group (daily 12 µg/kg follistatin plus 2 mg/kg TGFβ receptor inhibitor), versus controls. ACTRII/TGFBR signaling inhibition preserved cardiac function by echocardiography and prevented an increase in brain natriuretic peptide (BNP). ACTRII/TGFBR inhibition resulted in increased phosphorylation (P) of Akt and decreased P-p38 mitogen-activated protein kinase (MAPK) in MI mice. In vitro, Akt contributed to P-SMAD2,3, P-p38, and BNP regulation in cardiomyocytes. ACTRII/TGFBR inhibition increased sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) levels and decreased unfolded protein response (UPR) markers in MI mice. ACTRII/TGFBR inhibition was associated with a decrease in cardiac fibrosis and fibrosis markers, connective tissue growth factor (CTGF), type I collagen, fibronectin, α-smooth muscle actin, and matrix metalloproteinase (MMP)-12 in MI mice. MSTN exerted a direct regulation on the UPR marker eukaryotic translation initiation factor-2α (eIf2α) in cardiomyocytes. Our study suggests that ACTRII ligand inhibition has beneficial effects on cardiac signaling and fibrosis after ischemic HF. NEW & NOTEWORTHY Activin type II receptor ligand inhibition resulted in preserved cardiac function, a decrease in cardiac fibrosis, improved SERCA2a levels, and a prevention of the unfolded protein response in mice with myocardial infarction.

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

“…Of interest, ACVR2B/Fc administration was able to completely preserve cardiac function in the presence of metastatic CRC. 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 76–78 . 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.…”

“…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.…”

Myokines and Heart Failure: Challenging Role in Adverse Cardiac Remodeling, Myopathy, and Clinical Outcomes

“…However, being a strong predictor of frailty, disability, and mortality sarcopenia occurs in patients with HFrEF in results of abundant molecular mechanisms including Smad2/3 signaling [ 101 , 104 ]. Probably, these controversies in the protective ability of myostatin relate to etiology (ischemic or nonischemic) of HF [ 105 , 106 ].…”

Deficiency of myostatin protects skeletal muscle cells from ischemia reperfusion injury

“…This was achieved using a soluble ACVR2B decoy receptor 19 or by inhibiting ACTRII/TGFBR signaling 47 , respectively. Interestingly, the latter presented an underlying mechanism we identified ourselves during transcriptome analysis in mice: the mentioned up-regulation of Atp2a2 in Mstn Ln/Ln mice with concurrent down-regulation in WT mice, which was paralleled by up-regulation of SERCA2a (translational product of Atp2a2 ) in the setting of cardioprotection after myocardial infarction in mice 47 . Additionally, Zhu et al 48 had previously linked SERCA2a activity to p38 MAPK signaling: in 2017, they studied the effects of IR on rat cardiac function.…”