# Role of Activin Type II receptor signaling in age-related heart failure

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $209,654

## Abstract

Project Summary/Abstract
 Heart failure (HF) is a major cause of morbidity and mortality in older adults, and currently represents
the leading cause of hospitalization in the elderly. Advanced age is one of the strongest risk factors for HF,
although why this is the case and whether it is possible to intervene in this process, remain unclear. In this
context, the role of Activin type II receptor (ActRII) ligands – and their potential catabolic effects in aging and
disease – has been a subject of intense interest and controversy in HF. There is a fundamental gap in our
understanding of how aging contributes to HF. Our over-arching hypothesis is that ActRII activation increases
with age as well as biomechanical cardiac stress, and contributes to cardiac dysfunction in multiple forms of
age-related HF. Our long-term goal is to understand the mechanisms linking ActRII signaling to cardiac
dysfunction and learn whether these pathways can be targeted for therapeutic benefit. The objective of the
current application is to examine the functional contribution of ActRII signaling in multiple age-related models
of HF, and to elucidate the underlying mechanisms. Our preliminary data suggest that activity of the ActRII
pathway increases with age, frailty, and HF in human cohorts, and with age and HF in mice. The increased
activity appears driven predominantly by Activin-A rather than other ligands. In mice, elevating Activin-A
levels was sufficient to cause cardiac dysfunction, while inhibition of the pathway in three distinct HF models
prevented or reversed HF. The translational importance of these findings is underscored by the existence of
pathway inhibitors currently in trials for other indications. The proposed work will be pursued in three
integrated Specific Aims. In Aim 1, we will use specific and effective gain- and loss-of-function models to
directly assess the role of ActRII signaling in HF, and to examine the role of ActRII in cardiomyocytes in vivo.
In Aim 2, we will elucidate the mechanism(s) by which ActRII leads to cardiac dysfunction. In Aim 3, we will
investigate the dynamic regulation of this pathway in biobanked samples from elderly patients with heart
failure using targeted mass spectrometry assays in collaboration with Dr. Steven Carr, Director of Proteomics
at the Broad Institute. The functional importance of correlative clinical data will be examined using in vivo
models, which will be supported by in vitro investigation of primary cardiomyocytes to elucidate the underlying
mechanisms. Our approach combines innovative hypotheses, technologies, unique animal models, and
translational work in relevant clinical populations with the complementary expertise of an outstanding team
of collaborating investigators. The proposed research is significant, because it is expected to advance our
understanding of age-related HF and delineate pathways relevant to aging and disease with the potential to
mitigate these clinically important conditions.

## Key facts

- **NIH application ID:** 10154063
- **Project number:** 3R01AG061034-02S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** ANTHONY ROSENZWEIG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $209,654
- **Award type:** 3
- **Project period:** 2019-02-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10154063

## Citation

> US National Institutes of Health, RePORTER application 10154063, Role of Activin Type II receptor signaling in age-related heart failure (3R01AG061034-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10154063. Licensed CC0.

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