Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy

• Published in: Acta neuropathologica communications Vol. 13; no. 1; pp. 83 - 15
• Main Authors: Riccardi, Veronica, Viscomi, Carlo Fiore, Sandri, Marco, D’Alessandro, Angelo, Dzieciatkowska, Monika, Stephenson, Daniel, Federti, Enrica, Hermann, Andreas, Salviati, Leonardo, Siciliano, Angela, Andolfo, Immacolata, Alper, Seth L., Ceolan, Jacopo, Iolascon, Achille, Vattemi, Gaetano, Danek, Adrian, Walker, Ruth H., Mensch, Alexander, Otto, Markus, Deschauer, Marcus, Armbrust, Moritz, Beninca’, Cristiane, Salari, Valentina, Fabene, Paolo, Peikert, Kevin, De Franceschi, Lucia
• Format: Journal Article
• Language: English
• Published: London BioMed Central 24.04.2025; BioMed Central Ltd; BMC
• Subjects: Aging, Premature - genetics; Aging, Premature - metabolism; Aging, Premature - pathology; Analysis; Animals; Autophagy; Autophagy - genetics; Autophagy - physiology; Biomedical and Life Sciences; Biomedicine; Creatine; Creatine kinase; Energy; Female; Genetic aspects; Humans; Inflammaging; Male; Metabolites; Metabolome; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; Nervous system diseases; Neuroacanthocytosis - genetics; Neuroacanthocytosis - metabolism; Neuroacanthocytosis - pathology; Neurology; Neurosciences; NF-kB; Pathology; Vesicular Transport Proteins - deficiency; Vesicular Transport Proteins - genetics; Metabolome; Inflammaging; Energy; Autophagy; NF-kB
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-025-01997-y

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.