Biology subjects

Guilbeau-Frugier, C.

Publications and source records attributed to Guilbeau-Frugier, C..

3 recordsLinked to original sources

bioRxiv2025

Sequential mitochondrial remodeling in cardiomyocytes drives diastolic dysfunction and transition to HFrEF in anthracycline-induced cardiotoxicity

Aims. Anthracycline-induced cardiotoxicity is a leading cause of heart failure (HF) in cancer survivors and is usually detected only once systolic dysfunction is established, when myocardial injury may already be advanced. Diastolic dysfunction may occur earlier, but its onset and cellular basis are unknown. We investigated the temporal emergence of diastolic dysfunction during doxorubicin (DOX) exposure and its link to the selective vulnerability of crest/subsarcolemmal mitochondria (SSM) at the cardiomyocyte (CM) surface. Methods and results. Using a clinically relevant chronic DOX protocol in adult mice, we performed longitudinal cardiac assessment from the first exposure, combining conventional echocardiography, tissue Doppler, and global longitudinal strain (GLS). Structural and molecular correlates were characterized by atomic force microscopy, transmission electron microscopy, and 3D-quantitative imaging of native cardiac tissue, spatially resolving the CM surface (SSM) from the interior (interfibrillar mitochondria, IFM) compartment. DOX impaired active myocardial relaxation from the first dose with prolonged isovolumic relaxation time and reduced mitral annular e', whereas passive filling (transmitral filling, left atrial size) was preserved. Ejection fraction remained normal, with an early reduction in GLS. This early relaxation defect coincided with selective remodeling of the surface crest/SSM architecture, evident as crest flattening and progressive SSM loss and with depletion of the crest/SSM determinants Ephrin-B1 and Claudin-5, whereas IFM were affected only later, upon cumulative exposure. Surface SSM injury was accompanied by early, spatially ordered PINK1/Parkin activation, engaging SSM before IFM, and by loss of the sarcolemmal Na+;/Ca2+; exchanger NCX1, likely impairing diastolic Ca2+ removal. In CM-specific Ephrin-B1-deficient mice, which lack mature crest/SSM, DOX precipitated an accelerated transition to HF with reduced ejection fraction. Conclusions. Impaired active relaxation is the earliest functional hallmark of anthracycline cardiotoxicity, underpinned by selective injury of the surface crest/SSM compartment and its Na+;/Ca2+; exchanger NCX1, while IFM and passive filling are initially spared. Diastolic assessment from the first anthracycline cycles may improve early detection and prevention of HF progression.

pathology↗

bioRxiv2021

The last battle of Anne of Brittany: solving mass grave through an interdisciplinary approach (paleopathology, anthropobiology, history, multiple isotopes and radiocarbon dating)

Mass graves are usually key historical markers with strong incentive for archeological investigations. The identification of individuals buried in mass graves has long benefitted from traditional historical, archaeological, anthropological and paleopathological techniques. The addition of novel methods including genetic, genomic and isotopic geochemistry have renewed interest in solving unidentified mass graves. In this study, we demonstrate that the combined use of these techniques allows the identification of the individuals found in two Breton historical mass graves, where one method alone would not have revealed the importance of this discovery. The skeletons likely belong to soldiers from the two enemy armies who fought during a major event of Breton history: the siege of Rennes in 1491, which ended by the wedding of the Duchess of Brittany with the King of France and signaled the end of the independence of the region. Our study highlights the value of interdisciplinary approaches with a particular emphasis on increasingly accurate isotopic markers. The development of the sulfur isoscape and testing of the triple isotope geographic assignment are detailed in a companion paper [1].

ecology↗

bioRxiv2019

Ephrin-B1 blocks adult cardiomyocyte proliferation and heart regeneration

AimsDeciphering the innate mechanisms governing the blockade of proliferation in adult cardiomyocytes (CMs) is challenging for mammalian heart regeneration. Despite the exit of CMs from the cell cycle during the postnatal maturation period coincides with their morphological switch to a typical adult rod-shape, whether these two processes are connected is unknown. Here, we examined the role of ephrin-B1, a CM rod-shape stabilizer, in adult CM proliferation and cardiac regeneration.\n\nMethods and resultsTransgenic- or AAV9-based ephrin-B1 repression in adult mouse heart led to substantial proliferation of resident CMs and tissue regeneration to compensate for apex resection, myocardial infarction (MI) and senescence. Interestingly, in the resting state, CMs lacking ephrin-B1 did not constitutively proliferate, indicative of no major cardiac defects. However, they exhibited proliferation-competent signature, as indicated by higher mononucleated state and a dramatic decrease of miR-195 mitotic blocker, which can be mobilized under neuregulin-1 stimulation in vitro and in vivo. Mechanistically, the post-mitotic state of the adult CM relies on ephrin-B1 sequestering of inactive phospho-Yap1, the effector of the Hippo-pathway, at the lateral membrane. Hence, ephrin-B1 repression leads to phospho-Yap1 release in the cytosol but CM quiescence at resting state. Upon cardiac stresses (apectomy, MI, senescence), Yap1 could be activated and translocated to the nucleus to induce proliferation-gene expression and consequent CM proliferation\n\nConclusionsOur results identified ephrin-B1 as a new natural locker of adult CM proliferation and emphasize that targeting ephrin-B1 may prove a future promising approach in cardiac regenerative medicine for HF treatment.\n\nSignificanceThe mammalian adult heart is unable to regenerate due to the inability of cardiomyocytes (CMs) to proliferate and replace cardiac tissue lost. Exploiting CM-specific transgenic mice or AAV9-based gene therapy, this works identifies ephrin-B1, a specific rod-shape stabilizer of the adult CM, as a natural padlock of adult CM proliferation for compensatory adaptation to different cardiac stresses (apectomy, MI, senescence), thus emphasizing a new link between the adult CM morphology and their proliferation potential. Moreover, the study demonstrates proof-of-concept that targeting ephrin-B1 may be an innovative therapeutic approach for ischemic heart failure.

physiology↗