System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Epublish

PubMed: 40275365 DOI: 10.1186/s40478-025-01997-y

Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy.

Acta Neuropathol Commun 13(1):83

Authors: Veronica Riccardi, Carlo Fiore Viscomi, Marco Sandri, Angelo D'Alessandro, Monika Dzieciatkowska, Daniel Stephenson, Enrica Federti, Andreas Hermann, Leonardo Salviati, Angela Siciliano, Immacolata Andolfo, Seth L Alper, Jacopo Ceolan, Achille Iolascon, Gaetano Vattemi, Adrian Danek, Ruth H Walker, Alexander Mensch, Markus Otto, Marcus Deschauer, Moritz Armbrust, Cristiane Beninca', Valentina Salari, Paolo Fabene, Kevin Peikert, Lucia De Franceschi

Affiliations

  • Department of Engineering for Innovative Medicine- DIMI, University of Verona, Verona, Italy.
  • Department of Bomedical Sciences, University of Padua, Padua, Italy.
  • Venetian Institute of Molecular Medicine, Padova, Italy.
  • Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA.
  • Translational Neurodegeneration Section "Albrecht Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany.
  • Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, Rostock, Germany.
  • United Neuroscience Campus Lund-Rostock (UNC), Rostock site, Rostock, Germany.
  • Clinical Genetics Unit, Department of Women's and Children's Health, University of Padova, Padova, Italy.
  • Pediatric Research Institute (IRP) - Fondazione Città della Speranza, Padova, Italy.
  • Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy.
  • Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy.
  • CEINGE Biotecnologie Avanzate Franco Salvatore, Napoli, Italy.
  • Division of Nephrology, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Department of Neuroscience, Biomedicine and Movement Science, University of Verona, Verona, Italy.
  • Neurologische Klinik und Poliklinik, LMU Klinikum, LMU München, München, Germany.
  • Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA.
  • Department of Neurology, Mount Sinai School of Medicine, New York City, NY, USA.
  • Department of Neurology, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany.
  • Department of Neurology, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, München, Germany.
  • Goethe University, University Hospital Frankfurt, Neurological Institute (Edinger Institute), Frankfurt am Main, Germany.
  • Goethe University, University Hospital Frankfurt, University Cancer Center (UCT) Frankfurt-Marburg, Frankfurt am Main, Germany.
  • Goethe University, University Hospital Frankfurt, Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany.
  • German Cancer Consortium (DKTK), Partner site Frankfurt / Mainz and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Mitochondria and Metabolism Imaging Core, Department of Endocrinology, University of California, Los Angeles, USA.
  • Section of Anatomy and Histology, Department of Excellence in Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
  • Department of Engineering for Innovative Medicine- DIMI, University of Verona, Verona, Italy.
  • Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy.

Abstract

VPS13A disease (chorea-acanthocytosis), is an ultra-rare autosomal recessive neurodegenerative disorder caused by mutations of the VPS13A gene encoding Vps13A. Increased serum levels of the muscle isoform of creatine kinase associated with often asymptomatic muscle pathology are among the poorly understood early clinical manifestations of VPS13A disease. Here, we carried out an integrated analysis of skeletal muscle from Vps13a -/- mice and from VPS13A disease patient muscle biopsies. The absence of Vps13A impaired autophagy, resulting in pathologic metabolic remodeling characterized by cellular energy depletion, increased protein/lipid oxidation and a hyperactivated unfolded protein response. This was associated with defects in myofibril stability and the myofibrillar regulatory proteome, with accumulation of the myocyte senescence marker, NCAM1. In Vps13a -/- mice, the impairment of autophagy was further supported by the lacking effect of starvation alone or in combination with colchicine on autophagy markers. As a proof of concept, we showed that rapamycin treatment rescued the accumulation of terminal phase autophagy markers LAMP1 and p62 as well as NCAM1, supporting a connection between impaired autophagy and accelerated aging in the absence of VPS13A. The premature senescence was also corroborated by local activation of pro-inflammatory NF-kB-related pathways in both Vps13a -/- mice and patients with VPS13A disease. Our data link for the first time impaired autophagy and inflammaging with muscle dysfunction in the absence of VPS13A. The biological relevance of our mouse findings, supported by human muscle biopsy data, shed new light on the role of VPS13A in muscle homeostasis.

MeSH

Genes, Autophagy, Muscles, Absenteeism, Aging, Myofibrils, Biopsy, Muscle, Skeletal

Cited by