The activin receptor type 2 (ACTRII) pathway is activated in ageing and heart failure (HF), and inhibition of this catabolic pathway is a potential therapeutic target for HF. “What’s particularly exciting to us is that ‘human versions’ of the two inhibitors we used for these studies have already been used in early-phase clinical trials for other indications, so we’re hopeful that they — or other inhibitors — could be re-purposed for HF,” comments Anthony Rosenzweig, senior investigator on the article now published in Sci. Transl Med.

First author, Jason Roh, and colleagues showed that circulating levels of follistatin-related protein 3 (FSTL3), a downstream regulator of ACTRII signalling and an indirect measure of pathway activity, are increased with human ageing, frailty and HF severity. In mice, increasing the circulating levels of activin A, a ligand for ACTRII, increased cardiac ACTRII signalling and impaired cardiac function. Of note, a murinized version of bimagrumab (CDD866), a monoclonal antibody that blocks ACTRIIA and ACTRIIB and which is currently under clinical testing for sarcopenia, improved subclinical left ventricular systolic dysfunction in aged mice. Moreover, in a mouse model of HF induced by transverse aortic constriction (TAC), CDD866 improved systolic function and reduced pulmonary oedema. Cardiomyocyte-specific Acvr2b–/– (encoding ACTRIIB) mice were protected from systolic dysfunction after TAC. Finally, the investigators showed that one mechanism of action of ACTRII signalling might be via E3 ubiquitin-protein ligase SMURF1-dependent ubiquitination and subsequent proteasome-dependent degradation of SERCA2, a vital component of the cardiomyocyte Ca2+-handling machinery.

“Activin signalling … could help the energy-starved failing heart to compensate early on by inhibiting growth and ATP utilization, but chronic activation becomes deleterious,” suggests Rosenzweig, similar to the maladaptive activation of the renin–angiotensin–aldosterone system in HF. “Disrupting this downward spiral mediates substantial benefit in animal models, and we hope to test whether similar benefits could be attained in clinical HF,” he concludes.