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

Karlsson, Lars; González-Alvarado, María Nazareth; Larrosa-Flor, Mar; Osman, Ahmed; Börjesson, Mats; Blomgren, Klas; Kuhn, H. Georg

doi:10.1016/j.neuroscience.2018.05.036

Cited by 6 publications

(19 citation statements)

References 306 publications

(443 reference statements)

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“…The transgenic mouse model used in this study has a moderate overexpression of PGC-1α and its downstream effector genes Fndc5, Vegfb, IL15, Timp4, and Ctsb [34,35] and displays an endurance muscle phenotype with high mitochondrial density [34]. In this study, we observed a 3-4-fold increase in PGC-1α protein expression in gastrocnemius of transgenic sedentary female and male animals.…”

Section: Discussionsupporting

confidence: 49%

“…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.…”

Section: Resultsmentioning

confidence: 99%

“…Genotyping was performed as described previously [34]. Primers targeting interleukin 2 (internal control; forward, (5′-CTAGGCCACAGAATTGAAAGATCT-3′; reverse, 5′-GTAGGTGGAAATTCTAGCATCATCC-3′) and the PGC-1α transgene insert (forward, 5′-AGCCGTGACCACTG ACAACGAG-3′; reverse, 5′-GCTGCATGGTTCTG AGTGCTAAG-3′) were used for genotyping.…”

Section: Genotypingmentioning

confidence: 99%

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

et al. 2020

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Physical exercise can improve age-dependent decline in cognition, which in rodent is partly mediated by restoration of an age-dependent decline in neurogenesis. Exercise-inducible myokines in the circulation present a link in muscle-brain crosstalk. The transcription factor PGC-1α regulates the release of such myokines with neurotrophic properties into the circulation. We study how chronic muscular overexpression of PGC-1α could contribute to exercise-induced effects on hippocampal neurogenesis and if this effect could be enhanced in a running wheel paradigm. We used 3- and 11-month-old transgenic mice with overexpression of PGC-1α under the control of muscle creatinine kinase promoter (MCK-PGC-1α), which have a constitutively developed endurance muscle phenotype. Wild-type and MCK-PGC-1α mice were single housed with free access to running wheels. Four weeks of running in female animals increased the levels of newborn cells, immature neurons, and, for young animals, new mature neurons, compared to sedentary controls. However, no difference in these parameters was observed between wild-type and transgenic mice under sedentary or running conditions. Multiplex analysis of serum cytokines, chemokines, and myokines suggested several differences in serum protein concentrations between genotypes with musclin found to be significantly upregulated 4-fold in male MCK-PGC-1α animals. We conclude that constitutive muscular overexpression of PGC-1α, despite systemic changes and difference in serum composition, does not translate into exercise-induced effects on hippocampal neurogenesis, independent of the age of the animal. This suggests that chronic activation of PGC-1α in skeletal muscle is by itself not sufficient to mimic exercise-induced effects or to prevent decline of neurogenesis in aging.

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Section: Discussionsupporting

confidence: 49%

Section: Resultsmentioning

confidence: 99%

Section: Genotypingmentioning

confidence: 99%

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

et al. 2020

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“…008231), a kind gift from Dr. Bruce Spiegelman (Harvard Medical School, Boston, MA), have been previously described 9 . Housing and breeding conditions have been described previously 31 . All experiments were approved by the Gothenburg ethical committee on animal research (#317-2012 and #181-2015) and were performed in accordance with relevant guidelines and regulations.…”

Section: Methodsmentioning

confidence: 99%

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

Karlsson

González-Alvarado

Motalleb

et al. 2019

Sci Rep

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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.

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“…The statistical significance of the observed difference in western blot analysis was determined by parametric (Welch's t) or non-parametric (Mann-Whitney test) tests when data failed the Shapiro-Wilk normality test. Mass spectrometry data (LF) statistical significance was determined by the unpaired Student's t-test and differences were considered statistically significant at Benjamini-Hochberg corrected p-value (FDR)<0.05 [44].…”

Section: Statistical Analysesmentioning

confidence: 99%

New label-free methods for protein relative quantification applied to the investigation of an animal model of Huntington Disease

et al. 2020

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Spectral Counts approaches (SpCs) are largely employed for the comparison of protein expression profiles in label-free (LF) differential proteomics applications. Similarly, to other comparative methods, also SpCs based approaches require a normalization procedure before Fold Changes (FC) calculation. Here, we propose new Complexity Based Normalization (CBN) methods that introduced a variable adjustment factor (f), related to the complexity of the sample, both in terms of total number of identified proteins (CBN(P)) and as total number of spectral counts (CBN(S)). Both these new methods were compared with the Normalized Spectral Abundance Factor (NSAF) and the Spectral Counts log Ratio (Rsc), by using standard protein mixtures. Finally, to test the robustness and the effectiveness of the CBNs methods, they were employed for the comparative analysis of cortical protein extract from zQ175 mouse brains, model of Huntington Disease (HD), and control animals (raw data available via ProteomeXchange with identifier PXD017471). LF data were also validated by western blot and MRM based experiments. On standard mixtures, both CBN methods showed an excellent behavior in terms of reproducibility and coefficients of variation (CVs) in comparison to the other SpCs approaches. Overall, the CBN(P) method was demonstrated to be the most reliable and sensitive in detecting small differences in protein amounts when applied to biological samples.

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

Cited by 6 publications

References 306 publications

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

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

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

New label-free methods for protein relative quantification applied to the investigation of an animal model of Huntington Disease

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