Pérez-Schindler, Joaquín. Regulation of skeletal muscle plasticity by the transcriptional coregulators PGC-1α and NCoR1. 2013, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_10641
To define the role of NCoR1 in skeletal muscle plasticity and to identify its potential interplay with PGC-1alpha, we initially characterized NCoR1 muscle-specific knockout (mKO) mice. We observed that the deletion of NCoR1 in skeletal muscle resulted in enhanced oxygen consumption (VO2) during exercise, lower maximal force and increased ex vivo fatigue resistance. Interestingly, microarray analysis of NCoR1 mKO and PGC-1alpha muscle-specific transgenic (mTg) mice skeletal muscle revealed an up-regulation of genes related to oxidative metabolism in both mouse models. Consistently, we found that PGC-1alpha knockdown in cultured myotubes inhibited the up-regulation of mitochondrial enzymes induced by NCoR1 knockdown. Moreover, ERRalpha and PPARbeta/delta were identified as direct targets of both NCoR1 and PGC-1alpha. However, only the inhibition of ERRalpha was able to block the effects of NCoR1 knockdown in myotubes. Next, during the second study, the interplay between PGC-1alpha and PPARbeta/delta was determined by using different genetic mouse models. Surprisingly, our data demonstrated that the PGC-1alpha-PPARbeta/delta axis does not control whole body metabolism under basal conditions. Actually, PPARbeta/delta was found to be dispensable for the positive effects of PGC-1alpha on whole body (e.g. VO2) and skeletal muscle oxidative metabolism. Altogether, these studies demonstrate that, under basal conditions, NCoR1 and PGC-1alpha modulate skeletal muscle oxidative metabolism specifically by controlling ERRalpha-mediated gene expression.
Finally, skeletal muscle remodelling induced by chronic overload was studied by using the model of synergist ablation (SA). Interestingly, SA has been shown to induce skeletal muscle hypertrophy through the activation of the mammalian target of rapamycin complex 1 (mTORC1), while mTORC1 can enhance skeletal muscle oxidative metabolism by regulating the PGC-1alpha-Ying Yang 1 complex. Accordingly, in the last study of this thesis the potential function of the mTORC-1-PGC-1alpha axis in SA-induced skeletal muscle remodelling was defined by using PGC-1alpha mTg and mKO mice. As expected, SA strongly induced mTORC1 activation and skeletal muscle hypertrophy, though these effects were independent of PGC-1alpha. Moreover, SA down-regulated PGC-1alpha mRNA levels, consistent thus with the global repression of glycolytic and oxidative metabolism. Functional analyses further demonstrated that, SA promoted a switch toward a slow-contractile phenotype characterized by lower peak force and higher fatigue resistance, which was not altered in PGC-1alpha mTg mice. However, genetic ablation of PGC-1alpha preserved peak force after SA, an effect that seems to be related to the regulation of myosin heavy chain 2B, myosin regulatory light chain (MLC) and MLC kinase 2 by PGC-1alpha. Hence, we have found that PGC-1alpha is not involved in skeletal muscle hypertrophy and metabolic remodelling induced by SA, while this coactivator seem to be partially involved in the functional adaptations to SA. However, SA did not fully resemble the effects of resistance exercise in human skeletal muscle, thus the relevance of PGC-1alpha as a therapeutic target aiming at promoting skeletal muscle growth remains to be further explored under different conditions.
Therefore, the studies performed during this thesis have revealed new molecular mechanisms by which coregulators mediate skeletal muscle plasticity, especially related with the control of oxidative metabolism. Considering the relevance of skeletal muscle metabolic fitness in the development and prevention of metabolic diseases, these data has direct biomedical relevance. However, the therapeutic potential of the mechanisms here described remain to be defined in future studies.
|Committee Members:||Rüegg, Markus A.|
|Faculties and Departments:||03 Faculty of Medicine > Departement Biomedizin > Associated Research Groups > Pharmakologie (Handschin)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||142 S.|
|Last Modified:||30 Jun 2016 10:54|
|Deposited On:||29 Jan 2014 14:25|
Repository Staff Only: item control page