CtBP1 sustains activity-dependent muscle properties and dampens synaptic, contractile and metabolic changes triggered by denervation

Article Article scientifique Article CtBP1 sustains activity-dependent muscle properties and dampens synaptic, contractile and metabolic changes triggered by denervation eng 2026-03-23 2026-03-23 author Cattaneo Olivia Simone Allegra Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, CH-1211, Switzerland. 931399 Département de génétique et évolution (Genev) (BIANI) author Lopez Gaëtan Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, CH-1211, Switzerland. 419204 Département de physiologie cellulaire et métabolisme (PHYME) author Rajendra Jayasimman Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, CH-1211, Switzerland. 974601 author Chabry Florent Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, CH-1211, Switzerland. 883080 Département de physiologie cellulaire et métabolisme (PHYME) author Liaudet Nicolas 0000-0002-0749-5857 Bioimaging Core Facility, Faculty of Medicine, University of Geneva, Geneva, 1211, Switzerland. 862067 Services communs de la faculté de médecine (SCMU) author Startchik Sergei Bioimaging Core Facility, Faculty of Medicine, University of Geneva, Geneva, 1211, Switzerland. 27116 Services communs de la faculté de médecine (SCMU) author Prola Alexandre Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, CH-1211, Switzerland. 934539 author Castets Perrine Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, CH-1211, Switzerland. perrine.castets@unige.ch. 930953 Département de physiologie cellulaire et métabolisme (PHYME) 19 10.1186/s13395-026-00421-w 41872887 2044-5040 PMC13130457 https://link.springer.com/10.1186/s13395-026-00421-w Background: Denervation triggers dramatic atrophy of skeletal muscle, accompanied by synaptic, contractile and metabolic changes. Several factors were shown to contribute to genetic reprogramming and proteostasis changes after denervation. However, the mechanisms underlying the coordinated regulation of denervation-induced muscle fiber remodeling remain misunderstood. Methods: We investigated the role of the transcriptional co-repressor CtBP1 in the regulation of denervation-induced responses in muscle fibers. To this end, we analyzed its expression and localization in innervated and denervated muscles and assessed the consequences of its knockdown induced in vivo with AAV9, on synaptic, contractile and metabolic properties of muscle fibers. Results: CtBP1 was present both in sub- and non-synaptic myonuclei in innervated muscle. Although CtBP1 levels remained unchanged in denervated muscle, CtBP1 accumulated transiently in myonuclei after 2 days of denervation in TA/EDL muscles. Ctbp1 knockdown perturbed the expression of a large set of activity-independent and -dependent genes in innervated and denervated skeletal muscles. Reducing CtBP1 levels had limited effect on the expression of most synaptic genes, but increased transcript levels of Chrne, encoding the adult ε sub-unit of acetylcholine receptors (AChR). However, it did not affect AChR turnover or maintenance of the post-synaptic compartment upon denervation. Importantly, we uncovered that Ctbp1 knockdown exacerbates denervation-induced changes in metabolic gene expression, including most genes encoding proteins of the respiratory chain complexes. Consistently, it induced a contractile shift towards slower fibers in innervated fast muscle, mimicking denervation, and enhanced the denervation-induced metabolic transition towards oxidative slow-twitch fibers. Moreover, Ctbp1 knockdown precipitated the profound ultrastructural remodeling of mitochondria network induced after denervation. Conclusions: Our study unveils that CtBP1 sustains the innervated muscle pattern and antagonizes the effect of denervation on synaptic, contractile and metabolic muscle properties, with important implications for CtBP1-related muscle diseases. CtBP1 Denervation Fiber type Metabolism Mitochondria Skeletal muscle Dewey 612 Swiss National Science Foundation Physiology of neuromuscular junctions: Mechanisms underlying the maintenance and plasticity of synaptic structures in skeletal muscle 181102 CH 134 Département de physiologie cellulaire et métabolisme 21C false 1288 Muscle et jonction neuromusculaire 1007 https://doi.org/10.26037/yareta:t5p7zkd7z5btrid6ijkz6rgx2u Skeletal muscle 16 1 86b776a6-3317-448d-bb3b-2459eff30aa9 Article (Published version) Public s13395-026-00421-w.pdf 12970126 application/pdf CC BY-4.0 8fcdde2167a1a49bf2a537e249e967eb525366d4fe6c4c6c231043f8c20b9810 7c8ef2d0-07ba-4b01-9c28-dce0eaeefcbd Supplemental data Public 13395_2026_421_MOESM1_ESM.pdf 4746178 application/pdf 5133afd24c3ae34afd744c0257eb93267b18645086460c43aeb4e575ea22a29c openAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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CtBP1 sustains activity-dependent muscle properties and dampens synaptic, contractile and metabolic changes triggered by denervation	Skeletal muscle			2026	12	11

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Lopez, Gaëtan