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Abstract
Aerobic exercise prevents age-dependent decline in cognition and hippocampal neurogenesis. The transcription factor peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) mediates many of the exercise-induced benefits in skeletal muscle, including the release of factors into the circulation with neurotrophic effects. We use a transgenic mouse model with muscle-specific overexpression of PGC-1α to study the contribution of chronic muscle activation on exercise-induced effects on hippocampal neurogenesis in aging. Young and old transgenic and wild type animals of both sexes displayed a robust age-related reduction in newborn BrdU+-cells, immature neurons (DCX+-cells) and new mature BrdU+/NeuN+-neurons in the dentate gyrus. No differences were detected between genotypes or sexes. Analysis of serum proteins showed a tendency towards increased levels of myokines and reduced levels of pro-inflammatory cytokines for transgenic animals, but only musclin was found to be significantly up-regulated in transgenic animals. We conclude that constitutive muscular overexpression of PGC-1α, despite potent systemic changes, is insufficient for mimicking exercise-induced effects on hippocampal neurogenesis in aging. Continued studies are required to investigate the complex molecular mechanisms by which circulating signals could mediate exercise-induced effects on the central nervous system in disease and aging, with the aim of discovering new therapeutic possibilities for patients.
Highlights
Regular aerobic exercise, or endurance exercise, is a potent therapeutic treatment that apart from increasing well-being and general health, reduces the risk and treats a variety of chronic conditions in the body and brain, such as cardiovascular, metabolic, autoimmune, cerebrovascular, psychiatric, neurodegenerative diseases, and many others[1]
PGC-1α mediates these adaptations through interactions with many transcription factors such as peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and -delta (PPAR-delta), nuclear respiratory factor-1 and -2 (NRF1/2), estrogen-related receptor alpha (ERRα) and myocyte enhancer factor-2 (MEF2)[11]
For 11-month-old females and males, the number of newborn cells in the dentate gyrus (DG) subregions, we found no significant differences between genotypes or sexes in the granular cell layer (GCL) or molecular layer (ML) with the exception of a higher number of BrdU+ cells in the hilus for transgenic animals (two-way analysis of variance (ANOVA), n = 9–14; genotype effect, F(1, 39) = 5.4, p = 0.026; sex and interaction effect, n.s.; See Fig. 2)
Summary
Endurance exercise, is a potent therapeutic treatment that apart from increasing well-being and general health, reduces the risk and treats a variety of chronic conditions in the body and brain, such as cardiovascular, metabolic, autoimmune, cerebrovascular, psychiatric, neurodegenerative diseases, and many others[1]. Adult hippocampal neurogenesis occurs throughout life, but gradually diminishes during aging, a deterioration process considered to contribute to age-dependent cognitive decline[27,28] This decline in neurogenesis during aging can be ameliorated by different means including endurance exercise[29]. To determine if chronic activation of skeletal muscle along with improved muscle metabolism could prevent age-dependent decline in neurogenesis, we study hippocampal neurogenesis in young and middle-aged mice with overexpression of the transcription factor PGC-1α in skeletal muscle. To elucidate if chronic muscle activation could influence sex-dependent effects on hippocampal neurogenesis, we study both middle-aged female and male mice
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