title: Axonal domain disorganization in Caspr1 and Caspr2 mutant myelinated axons affects neuromuscular junction integrity, leading to muscle atrophy.
abstract: Bidirectional interactions between neurons and myelinating glial cells result in formation of axonal domains along myelinated fibers. Loss of axonal domains leads to detrimental consequences on nerve structure and function, resulting in reduced conductive properties and the diminished ability to reliably transmit signals to the targets they innervate. Thus, impairment of peripheral myelinated axons that project to the surface of muscle fibers and form neuromuscular junction (NMJ) synapses leads to muscle dysfunction. The goal of our studies was to determine how altered electrophysiological properties due to axonal domain disorganization lead to muscle pathology, which is relevant to a variety of peripheral neuropathies, demyelinating diseases, and neurodegenerative disorders. Using conventional Contactin-Associated Protein 1 (Caspr1) and Caspr2 single or double mutants with disrupted paranodal, juxtaparanodal, or both regions, respectively, in peripheral myelinated axons, we correlated defects in NMJ integrity and muscle pathology. Our data show that loss of axonal domains in Caspr1 and Caspr2 single and double mutants primarily alters distal myelinated fibers together with presynaptic terminals, eventually leading to NMJ denervation and reduction in postsynaptic endplate areas. Moreover, reduction in conductive properties of peripheral myelinated fibers together with NMJ disintegration leads to muscle atrophy in Caspr1 mutants or muscle fiber degeneration accompanied by mitochondrial dysfunction in Caspr1/Caspr2 double mutants. Together, our data indicate that proper organization of axonal domains in myelinated fibers is critical for optimal propagation of electrical signals, NMJ integrity, and muscle health, and provide insights into a wide range of pathologies that result in reduced nerve conduction leading to muscle atrophy. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Cellular and Integrative Physiology, Center for Biomedical Neuroscience, School of Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Julia
authors.initials: J
authors.lastname: Saifetiarova
authors.affiliation: Department of Cellular and Integrative Physiology, Center for Biomedical Neuroscience, School of Medicine, University of Texas Health Science Center, San Antonio, Texas.|Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cellular and Integrative Physiology, Center for Biomedical Neuroscience, School of Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Taylor
authors.affiliation: Department of Cellular and Integrative Physiology, Center for Biomedical Neuroscience, School of Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Cellular and Integrative Physiology, Center for Biomedical Neuroscience, School of Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Manzoor A
authors.identifier: 0000-0003-0989-1498
authors.initials: MA
authors.lastname: Bhat
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology* / Q000648:ultrastructure; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009133:Muscular Atrophy / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009413:Nerve Fibers, Myelinated / Q000473:pathology / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009431:Neural Conduction / Q000502:physiology; D009469:Neuromuscular Junction / Q000473:pathology* / Q000648:ultrastructure
chemical_list: C568163:CNTNAP2 protein, mouse; D015816:Cell Adhesion Molecules, Neuronal; C491322:Cntnap1 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins
keywords: axonal degeneration; axonal domains; muscle atrophy; myelinated fibers; nerve conduction; neuromuscular junction