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Constitutive PGC-1 alpha Overexpression in Skeletal Muscle Does Not Improve Morphological Outcome in Mouse Models of Brain Irradiation or Cortical Stroke

Journal article
Authors Lars O Karlsson
María Nazareth González-Alvarado
Mar Larrosa-Flor
A. Osman
Mats Börjesson
K. Blomgren
Hans-Georg Kuhn
Published in Neuroscience
Volume 384
Pages 314-328
ISSN 0306-4522
Publication year 2018
Published at Institute of Neuroscience and Physiology, Department of Health and Rehabilitation
Institute of Neuroscience and Physiology
Department of Food and Nutrition, and Sport Science
Pages 314-328
Language en
Links dx.doi.org/10.1016/j.neuroscience.2...
Keywords muscle, brain, exercise, PGC-1 alpha, FNDC5, irisin, transcriptional coactivator pgc-1-alpha, real-time pcr, mitochondrial, biogenesis, cerebral-ischemia, hippocampal neurogenesis, physical-exercise, oxidative stress, rat-brain, white fat, injury, Neurosciences & Neurology
Subject categories Neurosciences

Abstract

Physical exercise can improve morphological outcomes after ischemic stroke and ameliorate irradiation-induced reduction of hippocampal neurogenesis in rodents, but the mechanisms underlying these effects remain largely unknown. The transcription factor peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) is considered to be one of the central factors responsible for exercise-induced benefits in skeletal muscle, including the release of neurotrophic factors into the circulation. In order to test if PGC-1 alpha overexpression in skeletal muscle could simulate the exercise-induced effects on recovery after cranial irradiation and stroke, we used male adult transgenic mice overexpressing murine PGC-1 alpha under the control of muscle creatinine kinase promoter and subjected them to either whole brain irradiation at a dose of 4 Gy or photothrombotic stroke to the sensory motor cortex. Muscular PGC-1 alpha overexpression did not ameliorate irradiation-induced reduction of newborn BrdU-labeled cells in the dentate gyrus, immature neurons, or newborn mature neurons. In the stroke model, muscular overexpression of PGC-1 alpha resulted in an increased infarct size without any changes in microglia activation or reactive astrocytosis. No difference could be detected in the number of migrating neural progenitor cells from the subventricular zone to the lesioned neocortex or in vascular density of the contralateral neocortex in comparison to wildtype animals. We conclude that forced muscular overexpression of PGC-1 alpha does not have a beneficial effect on hippocampal neurogenesis after irradiation, but rather a detrimental effect on the infarct volume after stroke in mice. This suggests that artificial muscle activation through the PGC-1 alpha pathway is not sufficient to mimic exercise-induced recovery after cranial irradiation and stroke. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

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