Biology subjects

Peccate, C.

Publications and source records attributed to Peccate, C..

4 recordsLinked to original sources

bioRxiv2026

Axonopathy in Duchenne Muscular Dystrophy limits microdystrophin gene therapy efficacy

Duchenne muscular dystrophy (DMD) is classically defined as a primary myopathy, and current AAV-mediated microdystrophin gene therapies are shown to successfully preserve muscle integrity. However, their efficacy in recovering functional outcomes remains to improve. We hypothesized that this limitation stems from an unaccounted vulnerability within the peripheral nerve. Here, we demonstrate that the mdx mouse model exhibits a peripheral axonopathy independently of muscle necrosis. Using single-nucleus RNA sequencing and structural analyses, we have identified an active denervation program and a profound failure of neural repair pathways. Importantly, we revealed that the full-length dystrophin isoform Dp427c is expressed in the healthy peripheral nerve, intimately following the cytoskeletal organization and accumulating at regions of high biomechanical stress, including Schmidt-Lanterman incisures and Nodes of Ranvier. In its absence, nerves of mdx mice loss an essential scaffolding support, leading to localized structural collapse. Furthermore, we showed that muscle-restricted microdystrophin gene therapy rescues sarcolemmal integrity but failed to restore nerve-muscle connectivity or resolved neurotransmission defects. These findings fundamentally redefine DMD as an integrated motor unit pathology, thereby underscoring the absolute necessity of implementing combined therapeutic strategies that target both the muscle and the peripheral nervous system.

physiology↗

bioRxiv2025

Spatial and Multiomic profiling of muscle regeneration dynamics in Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a pediatric degenerative myopathy caused by the absence of functional dystrophin. As a result, DMD muscles exhibit compromised myofiber integrity and increased susceptibility to mechanical damage. In early disease stages, muscles undergo repeated cycles of degeneration and regeneration; over time, however, this regenerative capacity declines, leading to the gradual replacement of muscle tissue with fat and fibrosis. While several signaling pathways have been identified as deregulated in dystrophic muscle, the cellular and molecular mechanisms underlying this regenerative exhaustion remain to be fully elucidated. To address this, we constructed a comprehensive cellular atlas of human dystrophic muscle using high-resolution spatial transcriptomics (Visium HD), capturing the cellular crosstalk within regenerative regions. Cell-to-cell communication analysis revealed activation of Notch signaling mediated by NOTCH3 in activated satellite cells. Immunostaining confirmed elevated NOTCH3 expression in both DMD patient samples and in the mdx mouse model at late disease stages. Silencing of NOTCH3 in primary myoblasts improved myogenic differentiation, pinpointing NOTCH3-mediated signaling as a contributor to regeneration impairment. To further dissect the dynamics of regeneration and infer the gene regulatory networks governing myogenic differentiation, we integrated paired snRNA-seq and snATAC-seq data from young, adult, and aged mdx mice. This analysis identified GLIS3 upregulation as an additional barrier to effective myogenesis. GLIS3 displayed an overall increase in dystrophic muscles, while silencing experiments enhanced differentiation in myoblasts. Together, our work reveals intrinsic defects in the dystrophic stem cell compartment that emerge during disease progression and hinder the execution of the myogenic program. These findings suggest NOTCH3 and GLIS3 as potential therapeutic targets to enhance regeneration and maintain muscle integrity in DMD. This study provides a high-resolution map of the dystrophic regenerative landscape and offers a valuable resource for future translational research.

cell biology↗

bioRxiv2025

The Mutated p.H222P A-type Lamins Drive Loxl2-Mediated Extracellular Matrix Remodeling in Both Patient-Derived Cardiomyocytes and Mouse Models of Dilated Cardiomyopathy

LMNA cardiomyopathy, caused by mutations in the LMNA gene, is a severe form of dilated cardiomyopathy characterized by arrhythmias, contractile dysfunction, and increased myocardial fibrosis, which impairs left ventricular function and predisposes to heart failure. While the disease has been well characterized, a lack of insight into the pathogenesis impeded the development of therapies. We here used patient-derived LMNA p.H222P cardiomyocytes (hiPSC-CMs) and their isogenic controls and a LmnaH222P/H222P mouse model to dissect abnormal cardiac mechanisms leading to the development of the disease. We showed that LMNA p.H222P hiPSC-CMs exhibit elevated diastolic calcium levels and hypocontractility. They displayed nuclear shape abnormalities, a hallmark of LMNA cardiomyopathy, associated with altered chromosome spatial organization and gene expression profiles. Using transcriptomic analysis, we further revealed that genes related to cardiac extracellular matrix (ECM) remodeling, deposition, and components are dysregulated in both LMNA p.H222P hiPSC-CMs and mutated mice, suggesting a conserved pathogenic mechanism across species. Conversely, molecular inhibition of Loxl2, a key component of the ECM establishment, preserved the cardiac function in vivo. Taken together, our findings suggest that targeting Loxl2 could be a promising therapeutic strategy to maintain cardiac function in LMNA cardiomyopathy.

pathology↗

bioRxiv2023

Setdb1 safeguards genome integrity in muscle stem cells to allow for regenerative myogenesis and inflammation

Modulations in chromatin structure orchestrate gene expression and direct stem cell fate. More specifically, the histone 3 lysine 9 Methyltransferase Setdb1 controls transcriptional repression to regulate pluripotency and self-renewal. While Setdb1 functions have been extensively studied in embryonic stem cells and in cancer cells, less is known on its role in adult stem cells in vivo. Here, we show that Setdb1 expression by adult muscle stem cells (MuSCs) is required for muscle tissue regeneration following acute injury. We find that SETDB1 represses the expression of the endogenous retroviruses (ERVs) family of transposable elements in MuSCs. ERV de-expression in Setdb1-null MuSCs prevents their amplification following exit from quiescence and promotes cell death. Multi-omics profiling further shows that the absence of SETDB1 in MuSCs leads to the activation of the DNA-sensing cGAS-STING pathway, entailing increased cytokine expression. In vivo, conditional disruption of Setdb1 in MuSCs provokes aberrant infiltration of inflammatory cells including the appearance of a pathological macrophage lineage. The ensuing histiocytosis is accompanied by necrosis of the newly formed muscle fibers which, in addition with the progressive loss of MuSCs, completely abolish skeletal muscle tissue repair. In contrast, disruption of Setdb1 gene in another muscle-resident cell type, the fibro-adipogenic progenitors (FAPs), does not impact regenerative inflammation. In conclusion, the control of genome stability by SETDB1 in an adult somatic stem cell is necessary for both its regenerative potential and an adequate inflammation regulating tissue repair.

cell biology↗