Effects of PGC1a-induced exercise adaptations in muscle on plasticity and recovery mechanisms in the CNS

Abstract

In this thesis, we sought to determine if muscle-derived exercise-induced signaling via PGC-1α muscle activation influences neuroplasticity under physiological or pathophysiological conditions. For this purpose, transgenic mice with muscle-specific overexpression of PGC-1α that display an endurance exercise muscle phenotype were evaluated in models of cranial irradiation and photothrombotic stroke, as well as in aging and in a voluntary running paradigm. We also measured the response on proliferation and differentiation of NSPCs from treatment with either serum from exercised and transgenic mice, or conditioned media from PGC-1α-transfected myocytes. In paper I, we found that muscular PGC-1α overexpression in mice did not ameliorate irradiation-induced reduction of neurogenesis and rather resulted in increased infarct size without any differences in inflammatory response. In paper II and paper III, animals of both sexes displayed robust age-related reductions, and exercise-induced increases, in hippocampal neurogenesis. No differences were detected in these measurements between the genotypes. Further, transgenic animals had increased levels of myokines and reduced levels of pro-inflammatory cytokines. In paper IV, mouse sera from exercised or transgenic animals had no effect on proliferation of NSPCs, while conditioned medium from PGC-1α-overexpressing myocytes slightly increased proliferation. No differences existed in differentiation from treatment with different mouse sera or conditioned media. We conclude that artificial chronic muscle activation through the PGC-1α pathway, despite potent systemic changes, does not translate into exercise-induced effects on hippocampal neurogenesis, and is not sufficient to mimic exercise-induced effects on recovery after cranial irradiation or stroke, or prevent age-related reduction in neurogenesis. Likewise, circulating factors in serum from exercised animals, or from animals with muscle-specific PGC-1α overexpression, are not sufficient to directly induce changes in proliferation or differentiation of NSPCs in vitro. Despite evidence indicating that exercise-induced factors from muscle and other tissues are capable of influencing brain function, our results highlight the difficulty in mimicking sustained effects of exercise on the brain. The study of PGC-1α and related molecular pathways, in muscle and other tissue, contributes to our understanding of mechanisms behind exercise-related benefits on the brain.