title: Sympathetic innervation controls homeostasis of neuromuscular junctions in health and disease.
abstract: The distribution and function of sympathetic innervation in skeletal muscle have largely remained elusive. Here we demonstrate that sympathetic neurons make close contact with neuromuscular junctions and form a network in skeletal muscle that may functionally couple different targets including blood vessels, motor neurons, and muscle fibers. Direct stimulation of sympathetic neurons led to activation of muscle postsynaptic β2-adrenoreceptor (ADRB2), cAMP production, and import of the transcriptional coactivator peroxisome proliferator-activated receptor γ-coactivator 1α (PPARGC1A) into myonuclei. Electrophysiological and morphological deficits of neuromuscular junctions upon sympathectomy and in myasthenic mice were rescued by sympathicomimetic treatment. In conclusion, this study identifies the neuromuscular junction as a target of the sympathetic nervous system and shows that sympathetic input is crucial for synapse maintenance and function.
authors.affiliation: Interdisciplinary Center for Neurosciences, Universität Heidelberg, 69120 Heidelberg, Germany; Institute of Molecular and Cell Biology, Hochschule Mannheim, 68163 Mannheim, Germany; Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany;
authors.forename: Muzamil Majid
authors.initials: MM
authors.lastname: Khan
authors.affiliation: Department of Physiology, Faculdade de Medicina de Ribeirão Preto, University of São Paulo, 14049-900 Ribeirão Preto, Brazil; Department of Biochemistry and Immunology, Faculdade de Medicina de Ribeirão Preto, University of São Paulo, 14049-900 Ribeirão Preto, Brazil;
authors.forename: Danilo
authors.initials: D
authors.lastname: Lustrino
authors.affiliation: Department of Physiology, Faculdade de Medicina de Ribeirão Preto, University of São Paulo, 14049-900 Ribeirão Preto, Brazil; Department of Biochemistry and Immunology, Faculdade de Medicina de Ribeirão Preto, University of São Paulo, 14049-900 Ribeirão Preto, Brazil;
authors.forename: Willian A
authors.initials: WA
authors.lastname: Silveira
authors.affiliation: Interdisciplinary Center for Neurosciences, Universität Heidelberg, 69120 Heidelberg, Germany; Institute of Molecular and Cell Biology, Hochschule Mannheim, 68163 Mannheim, Germany; Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany;
authors.forename: Franziska
authors.initials: F
authors.lastname: Wild
authors.affiliation: Interdisciplinary Center for Neurosciences, Universität Heidelberg, 69120 Heidelberg, Germany; Institute of Molecular and Cell Biology, Hochschule Mannheim, 68163 Mannheim, Germany; Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany;
authors.forename: Tatjana
authors.initials: T
authors.lastname: Straka
authors.affiliation: The John Walton Muscular Dystrophy Research Centre, Medical Research Council Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom;
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Issop
authors.affiliation: The John Walton Muscular Dystrophy Research Centre, Medical Research Council Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom;
authors.forename: Emily
authors.initials: E
authors.lastname: O'Connor
authors.affiliation: The John Walton Muscular Dystrophy Research Centre, Medical Research Council Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom;
authors.forename: Dan
authors.initials: D
authors.lastname: Cox
authors.affiliation: Institute of Applied Informatics, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Reischl
authors.affiliation: Developmental Neurobiology Laboratory, European Neuroscience Institute, 37077 Göttingen, Germany;
authors.forename: Till
authors.initials: T
authors.lastname: Marquardt
authors.affiliation: Department of Integrative Pathophysiology, Universität Heidelberg, 68167 Mannheim, Germany;
authors.forename: Dittmar
authors.initials: D
authors.lastname: Labeit
authors.affiliation: Department of Integrative Pathophysiology, Universität Heidelberg, 68167 Mannheim, Germany;
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
authors.affiliation: Commissariat a l'energie atomique, Institut de Biologie et Technologies de Saclay (iBiTec-S), Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), 91191 Gif-sur-Yvette Cedex, France; Institut des Neurosciences Paris-Saclay, UMR 9197, CNRS/Université Paris-Sud, 91190 Gif-sur-Yvette Cedex, France;
authors.forename: Evelyne
authors.initials: E
authors.lastname: Benoit
authors.affiliation: Commissariat a l'energie atomique, Institut de Biologie et Technologies de Saclay (iBiTec-S), Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), 91191 Gif-sur-Yvette Cedex, France; Institut des Neurosciences Paris-Saclay, UMR 9197, CNRS/Université Paris-Sud, 91190 Gif-sur-Yvette Cedex, France;
authors.forename: Jordi
authors.initials: J
authors.lastname: Molgó
authors.affiliation: The John Walton Muscular Dystrophy Research Centre, Medical Research Council Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom;
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.affiliation: Max Planck Institute for Medical Research, 69120 Heidelberg, Germany;
authors.forename: Veit
authors.initials: V
authors.lastname: Witzemann
authors.affiliation: Department of Physiology, Faculdade de Medicina de Ribeirão Preto, University of São Paulo, 14049-900 Ribeirão Preto, Brazil; Department of Biochemistry and Immunology, Faculdade de Medicina de Ribeirão Preto, University of São Paulo, 14049-900 Ribeirão Preto, Brazil;
authors.forename: Isis C
authors.initials: IC
authors.lastname: Kettelhut
authors.affiliation: Department of Physiology, Faculdade de Medicina de Ribeirão Preto, University of São Paulo, 14049-900 Ribeirão Preto, Brazil; Department of Biochemistry and Immunology, Faculdade de Medicina de Ribeirão Preto, University of São Paulo, 14049-900 Ribeirão Preto, Brazil;
authors.forename: Luiz C C
authors.initials: LC
authors.lastname: Navegantes
authors.affiliation: Department of Biomedical Sciences, University of Padua, 35121 Padua, Italy; Institute of Neuroscience, Padua Section, National Research Council, 35121 Padua, Italy tullio.pozzan@unipd.it r.rudolf@hs-mannheim.de.
authors.forename: Tullio
authors.initials: T
authors.lastname: Pozzan
authors.affiliation: Interdisciplinary Center for Neurosciences, Universität Heidelberg, 69120 Heidelberg, Germany; Institute of Molecular and Cell Biology, Hochschule Mannheim, 68163 Mannheim, Germany; Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany; tullio.pozzan@unipd.it r.rudolf@hs-mannheim.de.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Rudolf
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D015374:Biosensing Techniques; D002467:Cell Nucleus / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006262:Health; D006706:Homeostasis; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000294:innervation; D009422:Nervous System Diseases / Q000473:pathology*; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D015398:Signal Transduction; D013562:Sympathectomy; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D000242:Cyclic AMP
keywords: beta-agonists; cAMP; myasthenia; neuromuscular junction; sympathetic neurons