Constitutive PGC-1α Overexpression in Skeletal Muscle Does Not Improve Morphological Outcome in Mouse Models of Brain Irradiation or Cortical Stroke. (1st August 2018)

• Record Type: Journal Article
• Authors: Karlsson, Lars; González-Alvarado, María Nazareth; Larrosa-Flor, Mar; Osman, Ahmed; Börjesson, Mats; Blomgren, Klas; Kuhn, Hans Georg
• Is Part Of: Neuroscience. Volume 384(2018)
• Page Start: 314
• Page End: 328
• Publication Date: 2018-08-01
• Subjects: ANOVA analysis of variance -- BDNF brain-derived neurotrophic factor -- BSA bovine serum albumin -- DG dentate gyrus -- FNDC5 fibronectin type III domain-containing protein 5 -- GCL granule cell layer -- IR ionizing radiation -- MCK-PGC-1α transgenic mice overexpressing PGC-1α under muscle creatinine kinase promoter -- PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-alpha -- ROS radical oxygen species -- RT room temperature -- SGZ subgranular zone -- SVZ subventricular zone; muscle -- brain -- exercise -- PGC-1α -- FNDC5 -- irisin; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2018.05.036
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: PGC-1α overexpression in skeletal muscle does not protect against irradiation-induced reduction of neurogenesis. PGC-1α overexpression in skeletal muscle does not influence the inflammatory response in the CNS after stroke. PGC-1α overexpression in skeletal muscle is detrimental for the infarct volume after stroke. 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-1α) 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-1α 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-1α 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-1α 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-1α 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-1α 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-1α pathway is not sufficient to mimic exercise-induced recovery after cranial irradiation and stroke.