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  • In addition to PGC transcriptional co repressors such as NCO

    2021-07-29

    In addition to PGC1α, transcriptional co-repressors such as NCOR and RIP140 participate in oxidative muscle remodeling induced by exercise, whereby reductions in their expression and the resulting de-repression of downstream TFs activates oxidative gene expression (Seth et al., 2007, Yamamoto et al., 2011, Fan et al., 2013). Furthermore, exercise is known to directly induce the expression of TFs such as ERRγ and PPARδ, which can activate their target genes without changes in expression or activity of co-factors (Wang et al., 2004, Narkar et al., 2011, Rangwala et al., 2010). Therefore, exercise training could beneficially affect muscle remodeling independent of PGC1α/β. It has been shown that adult muscle PGC1α and PGC1β are dispensable for endurance exercise-induced oxidative muscle remodeling. However, the short-term (5 day) induction of a mature muscle cell cre driver in this model would allow for the incorporation of wild-type satellite Cefotaxime sodium salt during exercise-induced muscle regeneration, confounding the conclusion (Ballmann et al., 2016).
    Results
    Discussion The intrinsic pleiotropic nature of co-regulatory factors such as PGC1α/β creates a mechanistic challenge in deconstructing the role of individual TF targets. As PGC1s broadly affect muscle oxidative metabolism and performance, it becomes key to decipher the principal targets that mediate these effects. The muscle-specific PGC1α/β KO mouse provides a means to identify defining factors because of their ability to rescue defects resulting from PGC1α/β deficiency. Thus, via gain of function studies, we genetically establish a pivotal role for ERRγ in mitochondrial energy metabolism, as well as its epistatic relationship with PGC1α/β, in driving a broad oxidative platform. For example, while PKO mice show reduced gene expression in major mitochondrial energetic pathways (including OXPHOS, TCA cycle, and FAO metabolism), ERRγ overexpression significantly boosts expression of these genes in PKO muscle, as well as restoring a multitude of the previously mentioned mitochondrial energetic dysfunctions (Figure S4F). ERRγ overexpression also significantly improves exercise performance in PKO mice (by about 3-fold). Unexpectedly, PGC1 deficiency in muscle shows little change in vasculature or oxidative myofibers such that ERRγ overexpression enhances both into the realm of highly trained animals. This indicates that baseline vasculature and oxidative fiber determination are PGC1-independent pathways (Figure S4F). Voluntary exercise in PKO mice still confers many benefits (Figure S4F), suggesting that major adaptive functions of exercise, such as angiogenesis, mitochondrial biogenesis, and oxidative remodeling, can be elicited in absence of PGC1α/β as long as ERRγ-dependent signaling is intact. This suggests that ERRγ synthetic agonists could have substantial and predictable benefits in treatment of muscle disease when exercise (and/or PGC1α/β induction) is not possible or practical. Differences in phenotype severity in previous PGC1α/β double-knockout models appear to correlate with the efficiencies of the muscle depletion, suggesting that the absolute levels of PGC1α/β are important (Zechner et al., 2010, Rowe et al., 2013). The severely compromised muscle phenotype described here is similar to that shown in Zechner et al. (2010), in which both models efficiently deplete both PGC1α and PGC1β in muscle. While injury is considered a product of exercise, PKO mice show evidence of severe muscle damage even under sedentary conditions, indicating a basal role for PGC1α/β in this process. Although the exact mechanism causing muscle damage in PKO mice is not clear, mitochondrial energy deficit and increased ROS production are likely involved (Powers et al., 2011). Such damage is almost completely rescued by ERRγ overexpression, with mitochondrial ROS in HEPKO muscle fully restored to WT levels. This is associated with ERRγ-induced upregulation of antioxidant genes such as Sod2 and Gpx3 and suppression of developmental myosin heavy-chain genes Myh3 and Myh8.