Abstract/Summary

Cardiac ageing is characterized by a pathological remodelling due to an increase of DNA damage, oxidative stress and fibrosis that impair function, often leading to heart failure. Ageing is also associated with activation of the activin signalling pathway which contributes to cardiac dysfunction. Previous studies have shown that soluble activin receptor type IIB preserves cardiac function during ageing. However, the beneficial effects of this inhibition in cardiac disorders such as accelerated ageing remain unknown. We hypothesized that inhibition of the activin receptor would be beneficial for the pathological cardiac phenotype of the Ercc1Δ/− progeroid mouse model of accelerated ageing. The myostatin/activin pathway was inhibited from week seven to week sixteen by intraperitoneal injection (IP) with 10mg/kg of soluble activin receptor IIB twice a week. Mice were sacrificed at week 16 as this is the timepoint when death begins to occur. The study of the cardiac remodelling was investigated in histology. A RNA-seq study was performed to highlight the impaired processes in the Ercc1Δ/− progeroid mouse, and to understand the beneficial effect of the sActRIIB-treatment. We also investigated the inhibition of this signalling pathway in the ercc-1(tm1981) C. elegans worms, to understand its effect on global ageing. Our study displayed that the soluble activin receptor type IIB reduced the oxidative stress level and double-strand break DNA in the Ercc1Δ/− progeroid mouse, but also reduced interstitial collagen I deposition and induced cardiomyocyte hypertrophy in the Ercc1Δ/− progeroid mouse. The RNA-seq analysis allows us to highlight the disruption of the circadian clock and the aberrant activation of the immune system inducing a chronic inflammation state in the Ercc1Δ/− progeroid mouse. The sActRIIB-treatment decreased this inflammatory condition in the Ercc1Δ/− progeroid and control mice. However, the circadian clock impairment remains unchanged. In the C. elegans worms, we dissected the Daf-4/ActRIIB signalling pathway activation by silencing the different co-receptors Daf-1 and Sma-6 with double-stranded RNA interferences. We investigated the impact of these pathways inhibition on global ageing by measuring the worms’ motility. The Daf-1 and Sma-6 RNAi was shown to be beneficial in the ercc-1(tm1981) C. elegans worms in comparison to the N2 worms.