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

Guilbeau-Frugier, C.; KARSENTY, C.; CAUQUIL, M.; LACHAIZE, V.; LAIREZ, O.; DAGUE, E.; SEVERAC, C.; PATALUCH, N.; SENARD, J.-M.; GALES, C.

doi:10.64898/2025.12.05.692508

bioRxiv · 10.64898/2025.12.05.692508

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

Guilbeau-Frugier, C.·KARSENTY, C.·CAUQUIL, M.·LACHAIZE, V.·LAIREZ, O.·DAGUE, E.·SEVERAC, C.·PATALUCH, N.·SENARD, J.-M.·GALES, C.

View original source ↗Export metadata ↓

Abstract

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.

Explore related subjects

pathology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Guilbeau-Frugier, C., KARSENTY, C., CAUQUIL, M., LACHAIZE, V., LAIREZ, O., DAGUE, E., SEVERAC, C., PATALUCH, N., SENARD, J.-M., GALES, C.. 2025-12-09. Sequential mitochondrial remodeling in cardiomyocytes drives diastolic dysfunction and transition to HFrEF in anthracycline-induced cardiotoxicity. https://doi.org/10.64898/2025.12.05.692508

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Prevention of Unc13a cryptic splicing is sufficient to preserve memory

TDP-43 dysfunction is thought to underlie frontotemporal dementia and limbic-predominant age-related TDP-43 encephalopathy, neurodegenerative dementias currently without effective therapy. Therapeutic strategies are designed to correct individual cryptic targets of TDP-43, such as UNC13A, whereby its cryptic splicing compromises synaptic function, yet the sufficiency of such an approach to prevent memory deficits is unclear. Using a forebrain neuron-specific TDP-43 knockout mouse model that recapitulates TDP-43 dysfunction occurring during early stages of human disorders, we found here that prevention of cryptic splicing to include that of Unc13a attenuated memory deficits. We show that genetic ablation of Unc13a cryptic exon solely in such TDP-43 knockout mice is sufficient to preserve cognition, supporting the clinical value of targeting UNC13A to mitigate memory deficits. Prevention of cryptic splicing of multiple targets of TDP-43 additionally attenuate neuron loss. For optimal outcomes in TDP-43 related dementias, these findings thus strongly support strategies designed to repress cryptic splicing of multiple targets of TDP-43, including UNC13A.

pathology↗

bioRxiv2026

Social-Cognitive Dysregulation Model of Misophonia: Perspective from a Behavioural Study

Misophonia is increasingly conceptualized as more than a disorder of sound tolerance, with trigger over-reactivity shaped by the social meaning of sounds, inferred intentions, and representations of others actions. We tested a social-cognitive dysregulation model of misophonia in (N = 341) adults using behavioural measures of Theory of Mind and emotion recognition, alongside measures of reflective functioning, empathy, alexithymia, and mimicry. Dimensional associations with misophonia severity and its five different dimensions were examined while accounting for age, sex, sound sensitivity, and anxiety/depressive symptoms. Increased misophonia severity was associated with less accurate and slower mental-state inference and emotion recognition. ToM accuracy effects were evident for more complex, cognitive, and affective mentalizing, but not for simpler mentalizing or physical control judgments, while emotion-recognition accuracy differences emerged for positive but not negative stimuli. Greater severity was also characterized by reduced certainty and greater uncertainty about mental states, greater difficulty identifying one s own feelings, and elevated alexithymia, whereas global self-reported empathy was largely preserved. Misophonia severity further predicted a greater propensity to mimic trigger-producing actions or sounds; 41% of participants exceeding the S-Five clinical cutoff (> 87) endorsed mimicry, which was particularly associated with a subjective restoration of control. Findings remained robust following influential-case sensitivity analyses. These results reveal a selective disturbance in self-other representation spanning mentalizing, emotion decoding, emotional self-representation, and embodied regulatory processes. They position misophonia within a broader social-cognitive framework in which auditory-affective reactivity may intersect with altered inferential and sensorimotor processing, while stopping short of causal inference.

pathology↗

bioRxiv2026

Lamin A/C depletion from myofibers and satellite cells in mice reveals selective muscle pathology

Mutations in the laminA/C gene (LMNA), which encodes the nuclear lamina proteins lamin A and lamin C (lamin A/C), have been linked to different human diseases affecting different tissues. Most LMNA mutations cause cardiomyopathy and muscular dystrophy, such as autosomal dominant Emery-Dreifuss muscular dystrophy. Recent studies to understand striated muscle laminopathies have taken advantage of Lmna conditional knockout mice to examine the effects of lamin A/C depletion in cardiomyocytes and cardiac fibroblasts. However, the role of lamin A/C in skeletal muscle has largely been uncharacterized using conditional knockout mice. We used different mouse lines to deplete lamin A/C from specific cell types in striated muscle. Lamin A/C depletion from fetal myofibers and cardiomyocytes led to no observable phenotype in the skeletal muscles despite leading to dramatic heart dilation and early lethality. Depletion of lamin A/C from both skeletal myofibers and satellite cells was lethal, with the most dramatic myopathic abnormalities observed in the intrinsic muscles of the tongue. The presence of lamin A/C in skeletal muscle satellite cells prevented the development of lethal myopathy when the proteins were deleted only from differentiated myofibers. Overall, our results provide a foundation for understanding the roles of lamin A/C in muscle maintenance and development, including the variable skeletal muscle involvement and much more invariant cardiomyopathy in patients with LMNA mutations.

pathology↗