Constitutive PGC-1α overexpression in skeletal muscle does not protect from age-dependent decline in neurogenesis

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.

WITHDRAWN: Silent information regulator 1 ameliorates oxidative stress injury via PGC-1α/PPARγ-Nrf2 pathway after ischemic stroke in rat.

“…SIRT also plays roles in modulating histone and nonhistone substrates, including DNA repair proteins and transcription factors (e.g., p53, nuclear factor-κB, and PGC-1α) [32]. PGC-1α is a central regulator of cellular pathways and has a variety of effects in multiple organs, including the kidneys, brain, and skeletal muscle [12,33,34]. Moreover, PGC-1α is a co-activator of a variety of transcription factors, including nuclear receptors, such as the thyroid hormone receptor, estrogen receptor, estrogen-related receptor α, and PPARγ [35,36].…”

Metabolic regulation of neurodifferentiation in the adult brain

“…Exercise is a well-known activator of mitochondrial biogenesis and has been suggested to trigger adult neurogenesis [168,169]. However, overexpression of PGC1α in skeletal muscle had no effect on age-associated decline of NSCs [170], despite improved muscle performance and increased levels of the neuroplasticity promoting brain-derived neurotrophic factor, BDNF [168]. Thus, the exact mechanism is not yet clear.…”

Constitutive PGC-1α Overexpression in Skeletal Muscle Does Not Contribute to Exercise-Induced Neurogenesis

“…In particular, we studied effects of exercise, aging and genotype on hippocampal neurogenesis. The MCK-PGC-1α mouse model used in this study has previously been validated by us to have a developed endurance muscle phenotype [ 34 , 35 ]. Western blot on gastrocnemius homogenate of middle-aged (7–10-month-old) sedentary animals show that MCK-PGC-1α animals have around 4-fold increased PGC-1α levels in comparison to wild-type animals ( t test with Welch correction, n = 3, p = 0.043; all female animals except for one male individual in WT sedentary; see Fig.…”

“…In cases where the concentrations were below the detection range, concentration value was set as midpoint between 0 and minimum detection limit of the analysis. In the multiplex protein analysis data of the study, sedentary animals from a previous study have been included as data points in the graphs for baseline purpose [ 35 ].…”