title: Autophagy impairment in muscle induces neuromuscular junction degeneration and precocious aging.
abstract: The cellular basis of age-related tissue deterioration remains largely obscure. The ability to activate compensatory mechanisms in response to environmental stress is an important factor for survival and maintenance of cellular functions. Autophagy is activated both under short and prolonged stress and is required to clear the cell of dysfunctional organelles and altered proteins. We report that specific autophagy inhibition in muscle has a major impact on neuromuscular synaptic function and, consequently, on muscle strength, ultimately affecting the lifespan of animals. Inhibition of autophagy also exacerbates aging phenotypes in muscle, such as mitochondrial dysfunction, oxidative stress, and profound weakness. Mitochondrial dysfunction and oxidative stress directly affect acto-myosin interaction and force generation but show a limited effect on stability of neuromuscular synapses. These results demonstrate that age-related deterioration of synaptic structure and function is exacerbated by defective autophagy.
authors.affiliation: Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine, 35129 Padova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carnio
authors.affiliation: Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine, 35129 Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: LoVerso
authors.affiliation: Laboratoire de Biologie Cellulaire du Vieillissement, UR4, Université Pierre et Marie Curie-Paris 6, 75252 Paris Cedex 05, France.
authors.forename: Martin Andres
authors.initials: MA
authors.lastname: Baraibar
authors.affiliation: Department of Molecular Medicine and Interuniversity Institute of Myology, University of Pavia, Via Forlanini 6, 27100 Pavia, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Longa
authors.affiliation: Institut für Angewandte Informatik, Karlsruhe Institute of Technology, 76128 Karlsruhe, Germany.
authors.forename: Muzamil Majid
authors.initials: MM
authors.lastname: Khan
authors.affiliation: Department of Molecular Medicine and Interuniversity Institute of Myology, University of Pavia, Via Forlanini 6, 27100 Pavia, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Maffei
authors.affiliation: Institut für Angewandte Informatik, Karlsruhe Institute of Technology, 76128 Karlsruhe, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Reischl
authors.affiliation: Department of Molecular Medicine and Interuniversity Institute of Myology, University of Pavia, Via Forlanini 6, 27100 Pavia, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Canepari
authors.affiliation: Ludwig Boltzmann Institute of Electrical Stimulation and Physical Rehabilitation, 1171 Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Loefler
authors.affiliation: Ludwig Boltzmann Institute of Electrical Stimulation and Physical Rehabilitation, 1171 Vienna, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Kern
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy.
authors.forename: Bert
authors.initials: B
authors.lastname: Blaauw
authors.affiliation: Laboratoire de Biologie Cellulaire du Vieillissement, UR4, Université Pierre et Marie Curie-Paris 6, 75252 Paris Cedex 05, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Friguet
authors.affiliation: Department of Molecular Medicine and Interuniversity Institute of Myology, University of Pavia, Via Forlanini 6, 27100 Pavia, Italy; Fondazione Salvatore Maugeri (IRCCS), Scientific Institute of Pavia, 27100 Pavia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bottinelli
authors.affiliation: Institut für Angewandte Informatik, Karlsruhe Institute of Technology, 76128 Karlsruhe, Germany; Institut für Toxikologie und Genetik, Karlsruhe Institute of Technology, 76128 Karlsruhe, Germany; Institut für Molekular und Zellbiologie, University of Applied Sciences Mannheim, 68163 Mannheim, Germany; Institut für Medizintechnologie, University of Applied Sciences Mannheim and University of Heidelberg, 68163 Mannheim, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Rudolf
authors.affiliation: Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine, 35129 Padova, Italy; Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy; Institute of Neuroscience, Consiglio Nazionale delle Ricerche, 35121 Padova, Italy; Department of Medicine, McGill University, Montreal QC H3A 0G4, Canada; Telethon Institute of Genetics and Medicine (TIGEM), 80131 Napoli, Italy. Electronic address: marco.sandri@unipd.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
mesh_terms: D000199:Actins / Q000378:metabolism; D000375:Aging; D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D002460:Cell Line; D006801:Humans; D008136:Longevity; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000378:metabolism; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology; D009218:Myosins / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism* / Q000648:ultrastructure; D018384:Oxidative Stress
chemical_list: D000199:Actins; C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D009218:Myosins; D000071193:Autophagy-Related Protein 7