Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy

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<sup>-/-</sup> 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<sup>-/-</sup> 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<sup>-/-</sup> 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.

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Journal
Acta Neuropathologica Communications
Published
2025-04-24
DOI
https://doi.org/10.1186/s40478-025-01997-y
Citations
2
Primary Topic
Endoplasmic Reticulum Stress and Disease
Type
article
Field-Weighted Citation Impact
2.30

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article

Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy

Ruth H. Walker, Angela Siciliano, Marcus Deschauer, Valentina Salari et al.
2 citations
Acta Neuropathologica Communications
Endoplasmic Reticulum Stress and Disease
2.30
article

Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy

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

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<sup>-/-</sup> 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<sup>-/-</sup> 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<sup>-/-</sup> 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.

Acta Neuropathologica CommunicationsVol. 13(1)
Goethe University Frankfurt (DE), University of Verona (IT), Beth Israel Deaconess Medical Center (US), Harvard University (US), University of Padua (IT), German Cancer Research Center (DE), Heidelberg University (DE), TUM Klinikum (DE), LMU Klinikum (DE), Veneto Institute of Molecular Medicine (IT), Azienda Ospedaliera Universitaria Integrata Verona (IT), James J. Peters VA Medical Center (US), CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) (IT), University Hospital Frankfurt (DE), Frankfurt Cancer Institute (DE), Città della Speranza Foundation (IT), University of Rostock (DE), Martin Luther University Halle-Wittenberg (DE), University of Naples Federico II (IT), MRC Mitochondrial Biology Unit (GB), Ludwig-Maximilians-Universität München (DE), University of Colorado Denver (US), Icahn School of Medicine at Mount Sinai (US)
U.S. Department of Veterans Affairs, Eli Lilly and Company, Advocacy for Neuroacanthocytosis Patients, Hermann und Lilly Schilling-Stiftung für Medizinische Forschung, Università degli Studi di Verona
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Openalex Percentile: Top 14%
Endoplasmic Reticulum Stress and Disease
2.30
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