title: Activation of Akt/FKHR in the medulla oblongata contributes to spontaneous respiratory recovery after incomplete spinal cord injury in adult rats.
abstract: After incomplete spinal cord injury (SCI), patients and animals may exhibit some spontaneous functional recovery which can be partly attributed to remodeling of injured neural circuitry. This post-lesion plasticity implies spinal remodeling but increasing evidences suggest that supraspinal structures contribute also to the functional recovery. Here we tested the hypothesis that partial SCI may activate cell-signaling pathway(s) at the supraspinal level and that this molecular response may contribute to spontaneous recovery. With this aim, we used a rat model of partial cervical hemisection which injures the bulbospinal respiratory tract originating from the medulla oblongata of the brainstem but leads to a time-dependent spontaneous functional recovery of the paralyzed hemidiaphragm. We first demonstrate that after SCI the PI3K/Akt signaling pathway is activated in the medulla oblongata of the brainstem, resulting in an inactivation of its pro-apoptotic downstream target, forkhead transcription factor (FKHR/FOXO1A). Retrograde labeling of medullary premotoneurons including respiratory ones which project to phrenic motoneurons reveals an increased FKHR phosphorylation in their cell bodies together with an unchanged cell number. Medulla infusion of the PI3K inhibitor, LY294002, prevents the SCI-induced Akt and FKHR phosphorylations and activates one of its death-promoting downstream targets, Fas ligand. Quantitative EMG analyses of diaphragmatic contractility demonstrate that the inhibition of medulla PI3K/Akt signaling prevents spontaneous respiratory recovery normally observed after partial cervical SCI. Such inhibition does not however affect either baseline contractile frequency or the ventilatory reactivity under acute respiratory challenge. Together, these findings provide novel evidence of supraspinal cellular contribution to the spontaneous respiratory recovery after partial SCI.
authors.affiliation: Aix-Marseille Université, INMED UMR 901, 13273 Marseille, France; INSERM, UMR 901, 13273 Marseille, France; Aix-Marseille Université, CNRS, CRN2M UMR 6231, 13397 Marseille, France.
authors.forename: M S
authors.initials: MS
authors.lastname: Felix
authors.affiliation: Aix-Marseille Université, INMED UMR 901, 13273 Marseille, France; INSERM, UMR 901, 13273 Marseille, France; Aix-Marseille Université, CNRS, CRN2M UMR 6231, 13397 Marseille, France.
authors.forename: S
authors.initials: S
authors.lastname: Bauer
authors.affiliation: Aix-Marseille Université, CNRS, CRN2M UMR 6231, 13397 Marseille, France.
authors.forename: F
authors.initials: F
authors.lastname: Darlot
authors.affiliation: Aix-Marseille Université, INMED UMR 901, 13273 Marseille, France; INSERM, UMR 901, 13273 Marseille, France.
authors.forename: F
authors.initials: F
authors.lastname: Muscatelli
authors.affiliation: Aix-Marseille Université, CNRS, CRN2M UMR 6231, 13397 Marseille, France; Aix-Marseille Université, PPSN EA 4674, 13013 Marseille, France.
authors.forename: A
authors.initials: A
authors.lastname: Kastner
authors.affiliation: Aix-Marseille Université, CNRS, CRN2M UMR 6231, 13397 Marseille, France; Aix-Marseille Université, CNRS, LNIA UMR 7260, 13331 Marseille, France.
authors.forename: P
authors.initials: P
authors.lastname: Gauthier
authors.affiliation: Aix-Marseille Université, INMED UMR 901, 13273 Marseille, France; INSERM, UMR 901, 13273 Marseille, France; Aix-Marseille Université, CNRS, CRN2M UMR 6231, 13397 Marseille, France. Electronic address: valery.matarazzo@inserm.fr.
authors.forename: V
authors.initials: V
authors.lastname: Matarazzo
mesh_terms: D000818:Animals; D002574:Cervical Vertebrae; D003964:Diaphragm / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D007839:Functional Laterality; D008526:Medulla Oblongata / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D009046:Motor Neurons / Q000473:pathology / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010791:Phrenic Nerve / Q000473:pathology / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D012119:Respiration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors; D000071161:Forkhead Box Protein O1
chemical_list: D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1
keywords: Cervical hemisection; Diaphragm; FKHR; FOXO1A; P-Akt; Plasticity