Circulating growth differentiation factor 11 exacerbates myocardial injury in mice and associates with increased infarct size in humans
Authors: Kraler S , Vdovenko D , Balbi C , Lapikova-Bryhinska T , Camici G G , Liberale L , Mach F , Bhasin S , Wenzl F A , Muller O , Raeber L , Matter C , Montecucco F , Luescher T F , Akhmedov A 
Published: November 2023

Abstract

Background
The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a TGF-β superfamily member that shares 90% homology with myostatin (MSTN), remains controversial. Here, we aimed to probe the role of GDF11 in acute myocardial infarction (MI), a frequent cause of heart failure and premature death during ageing.

Methods
Young (3-4 months) and old (22-24 months) C57Bl/6 mice were subjected to either systemic recombinant GDF11 (rGDF11; 0.1 mg/kg BW daily) or control treatment over 30 days before myocardial ischaemia-reperfusion (I/R) injury was induced. Dissected hearts underwent in-depth profiling that ranged from histological workup and the assessment of inflammatory pathways to cardiomyocyte viability testing and IPA-guided -omics. Key regulatory mechanisms were studied in vitro using human adult stromal cardiac-specific mesenchymal cells (cMSCs) and HL-1 cardiomyocytes. By harnessing liquid chromatography–tandem mass spectrometry (LC-MS/MS), plasma levels of GDF11/MSTN were determined in prospectively recruited patients with MI and the independent association with myocardial infarct size was estimated using hierarchical regression models.

Results
In contrast to endogenous Mstn, myocardial Gdf11 mRNA expression levels declined upon ageing, and were further reduced following I/R injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by rGDF11 delivery prior to myocardial I/R augmented rather than reduced infarct size in mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. By applying a targeted transcriptomics approach on dissected hearts subjected to I/R, we identified the mesenchymal marker Nkx2-5 to be blunted upon rGDF11 supplementation, pointing toward a cMSC-mediated mechanism. Accordingly, human cMSCs exposed to high rGDF11 in vitro showed similar reductions in NKX2-5 expression levels, coinciding with diminished anti-apoptotic effects conferred by resident cMSCs on HL-1 cardiomyocytes. Finally, by harnessing a highly-specific LC–MS/MS based assay, we show that in patients with MI receiving contemporary management circulating GDF11 but not MSTN levels inclined with age. Moreover, circulating GDF11 emerged as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels. Notably, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event.

Conclusions
Our data challenge the initially reported rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice by impinging on the cardioprotective effects of resident cMSCs. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of endogenous cardioprotective mechanisms and thus poor outcomes post-MI.