ERRGO mice exhibited increased oxygen consumption decreased
ERRGO mice exhibited increased oxygen consumption, decreased RER, high running endurance, and resistance to diet-induced weight gain. These changes are physiological hallmarks of increased aerobic capacity in mice and are a direct consequence of engineering highly oxidative and vascularized muscle by ERRγ. While similar remodeling of skeletal muscle and aerobic physiology are triggered by exercise, our data prove that generation of a fully functional “endurance vasculature” is not exercise dependent (Bloor, 2005, Egginton, 2009, Gavin et al., 2007, Gustafsson and Kraus, 2001, Jensen et al., 2004, Waters et al., 2004). Reciprocally, the extent to which ERRγ signaling in skeletal muscle contributes to exercise bupropion hydrochloride receptor remains to be determined. A surprising finding of our study was lack of change in the expression of PGC-1α, a known and inducible regulator of aerobic muscles, in the ERRγ-transformed muscle. One alternative possibility is posttranslational activation of PGC-1α without change in its expression (Jäger et al., 2007, Puigserver et al., 2001, Rodgers et al., 2005). Deacetylation of PGC-1α is critical for its activation in the skeletal muscle (Cantó et al., 2010, Gerhart-Hines et al., 2007, Lagouge et al., 2006). However, ERRγ overexpression did not lead to deacetylation of PGC-1α, which remained comparably acetylated in both the WT and ERRGO muscles. The lack of posttranslational activation of the cofactor in ERRGO mice is further underscored by a previous report that nongenomic activation of PGC-1α typically leads to its transcriptional induction, which we did not observe in these studies (Jäger et al., 2007). Along the same lines, it was recently shown that both PGC-1α and β are dispensable for fiber type specification in the skeletal muscle (Zechner et al., 2010). In contrast, we find that an alternative aerobic master regulator, AMPK, is activated by ERRγ in the skeletal muscles. AMPK is typically activated by exercise (Fujii et al., 2000, Winder and Hardie, 1996, Wojtaszewski et al., 2000) and is essential for exercise-mediated switch to aerobic myofibers in the skeletal muscle (Röckl et al., 2007). Indeed, transgenic activation of AMPK in the skeletal muscle increases the proportions of oxidative myofibers in absence of any exercise (Röckl et al., 2007). Similarly, we found that chemical activation of AMPK by AICAR triggers aerobic transformation of type II muscle. However, AMPK alone is unlikely to mediate all the ERRγ effects, and contribution by additional metabolic regulators (e.g., calcineurin, SIRT1, etc.) in ERRGO mice cannot be ruled out. This is possible because, unlike ERRγ, AMPK activation apparently does not lead to a complete transformation to a type I phenotype, but to more intermediate type IIa and IIx oxidative myofibers (Röckl et al., 2007). In this context, it is peculiar that we found AMPK to be naturally and selectively active in soleus (predominantly type I myofibers) compared to quadriceps (predominantly type II myofibers). Previous studies have suggested AMPK activity to be similar between soleus and EDL (also predominantly made up of type II myofibers) (Dzamko et al., 2008, Jensen et al., 2007, Jørgensen et al., 2004). Speculatively, this discrepancy may have technical attributes or may even be linked to possible differences in recruitment of EDL and quadriceps for postural activity that might affect basal AMPK activation. Nevertheless, our results demonstrate that in the context of overexpression, ERRγ is sufficient to initiate both metabolic and vascular pathways to drive aerobic remodeling of sedentary muscle independently of PGC-1α by recruiting alternative regulators such as AMPK (see Figure 6E). Multiple diseases, including obesity and diabetes, are commonly linked to deregulation of both oxidative metabolism and vascularity. A shared therapeutic approach to these conditions includes exercise that activates a plethora of transcriptional pathways to increase aerobic metabolism and vascularization to ultimately enhance performance (Bloor, 2005, Egginton, 2009, Gavin et al., 2007, Gustafsson and Kraus, 2001, Jensen et al., 2004, Waters et al., 2004). Our findings present a possibility of therapeutically exploiting ERRγ to simultaneously regulate oxidative capacity and vascularity. High expression levels of this receptor in tissues most prone to metabolic and vascular diseases (e.g., heart, skeletal muscle, brain, and kidney) further potentiates its value as a potential pharmacologic target (Ariazi et al., 2002, Cheung et al., 2005, Gao et al., 2006, Giguère, 2008, Heard et al., 2000, Hong et al., 1999). In summary, our studies show that ERRγ controls mitochondrial function and metabolism together with angiogenesis that anatomically synchronizes vascular arborization to oxidative metabolism.