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