ERRγ Promotes Angiogenesis, Mitochondrial Biogenesis, and Oxidative Remodeling in PGC1α/β-Deficient Muscle

Fan, Weiwei; He, Nanhai; Lin, Chengyan; Wei, Zong; Hah, Nasun; Waizenegger, Wanda; He, Ming Xiao; Liddle, Christopher; Yu, Ruth T.; Atkins, Annette R.; Downes, Michael; Evans, Ronald M.

doi:10.1016/j.celrep.2018.02.047

Cited by 61 publications

(47 citation statements)

References 32 publications

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“…ERRγ interacts with PGC‐1α and plays a central role in regulating the mitochondrial energy metabolism 62 . Notably, ERRγ overexpression promotes angiogenesis and mitochondrial biogenesis independently of PGC‐1α, resulting in increased oxidative remodeling of muscle fibers and increased exercise performance 39 . In this study, we found increased mRNA and protein expression of ERRγ in the mouse gastrocnemius muscle.…”

Section: Discussionsupporting

confidence: 50%

“…UPLC‐QTOF‐MS/MS analysis showed that U pinnatifida extracts contained hesperetin and caffeic acid (Figure S3). Present study intended to show the potential effects of fucoxanthin, hesperetin, and caffeic acid present in U pinnatifida extracts on the regulation of master regulators for exercise adaptation and skeletal muscle function 39 . Fucoxanthin increased protein expression of phospho‐AMPK, PGC‐1α, ERRγ, ERRα, SIRT1, and NRF2 in C2C12 myotubes (Figure 7A).…”

Section: Resultsmentioning

confidence: 97%

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Undaria pinnatifidaextract feeding increases exercise endurance and skeletal muscle mass by promoting oxidative muscle remodeling in mice

Ahn

et al. 2020

FASEB j.

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Dietary habits can alter the skeletal muscle performance and mass, and Undaria pinnatifida extracts are considered a potent candidate for improving the muscle mass and function. Therefore, in this study, we aimed to assess the effect of U pinnatifida extracts on exercise endurance and skeletal muscle mass. C57BL/6 mice were fed a 0.25% U pinnatifida extract‐containing diet for 8 weeks. U pinnatifida extract‐fed mice showed increased running distance, total running time, and extensor digitorum longus and gastrocnemius muscle weights. U pinnatifida extract supplementation upregulated the expression of myocyte enhancer factor 2C, oxidative muscle fiber markers such as myosin heavy chain 1 (MHC1), and oxidative biomarkers in the gastrocnemius muscles. Compared to the controls, U pinnatifida extract‐fed mice showed larger mitochondria and increased gene and protein expression of molecules involved in mitochondrial biogenesis and oxidative phosphorylation, including nuclear respiratory factor 2 and mitochondrial transcription factor A. U pinnatifida extract supplementation also increased the mRNA expression of angiogenesis markers, including VEGFa, VEGFb, FGF1, angiopoietin 1, and angiopoietin 2, in the gastrocnemius muscles. Importantly, U pinnatifida extracts upregulated the estrogen‐related receptor γ and peroxisome proliferator‐activated receptor gamma co‐activator 1‐alpha (PGC‐1α)/AMP‐activated protein kinase (AMPK)/sirtuin 1 (SIRT1) networks, which are partially increased by fucoxanthin, hesperetin, and caffeic acid treatments. Collectively, U pinnatifida extracts enhance mitochondrial biogenesis, increase oxidative muscle fiber, and promote angiogenesis in skeletal muscles, resulting in improved exercise capacity and skeletal muscle mass. These effects are attributable to fucoxanthin, hesperetin, and caffeic acid, bioactive components of U pinnatifida extracts.

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Section: Discussionsupporting

confidence: 50%

Section: Resultsmentioning

confidence: 97%

Undaria pinnatifidaextract feeding increases exercise endurance and skeletal muscle mass by promoting oxidative muscle remodeling in mice

Ahn

et al. 2020

FASEB j.

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“…Compared with IMAGE analysis in mTg mice ( S2 Table ), NFKB2, ZFP91, ATF4, and TBX15 were uniquely identified as causal factors in exercise. To verify motif predictions from our analyses, we compared genome-wide DNA binding sites of transgenically expressed Errg in Quad [40] to EMRs. Nearly 30% (778/2,662) of EMRs colocalized with ERRγ bound sites ( Fig 9F, left), in keeping with the strong enrichment of ERR/NR binding sites predicted in our motif analysis.…”

Section: Resultsmentioning

confidence: 99%

Dynamic enhancers control skeletal muscle identity and reprogramming

et al. 2019

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Skeletal muscles consist of fibers of differing metabolic activities and contractility, which become remodeled in response to chronic exercise, but the epigenomic basis for muscle identity and adaptation remains poorly understood. Here, we used chromatin immunoprecipitation sequencing of dimethylated histone 3 lysine 4 and acetylated histone 3 lysine 27 as well as transposase-accessible chromatin profiling to dissect cis-regulatory networks across muscle groups. We demonstrate that in vivo enhancers specify muscles in accordance with myofiber composition, show little resemblance to cultured myotube enhancers, and identify glycolytic and oxidative muscle-specific regulators. Moreover, we find that voluntary wheel running and muscle-specific peroxisome proliferator–activated receptor gamma coactivator-1 alpha (Pgc1a) transgenic (mTg) overexpression, which stimulate endurance performance in mice, result in markedly different changes to the epigenome. Exercise predominantly leads to enhancer hypoacetylation, whereas mTg causes hyperacetylation at different sites. Integrative analysis of regulatory regions and gene expression revealed that exercise and mTg are each associated with myocyte enhancer factor (MEF) 2 and estrogen-related receptor (ERR) signaling and transcription of genes promoting oxidative metabolism. However, exercise was additionally associated with regulation by retinoid X receptor (RXR), jun proto-oncogene (JUN), sine oculis homeobox factor (SIX), and other factors. Overall, our work defines the unique enhancer repertoires of skeletal muscles in vivo and reveals that divergent exercise-induced or PGC1α-driven epigenomic programs direct partially convergent transcriptional networks.

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“…PGC1α also controls the expression of Vegf and other pro-angiogenic genes by recruiting estrogen-related receptor α (ERRα) to conserved binding sites within their promoters (49,50). In contrast to Errγ, loss of Pgc1α does not affect baseline muscle capillary density (43,51), but mice lacking Pgc1α or Errα in myofibers fail to increase vascular density in response to exercise (50,52). Even though PGC1α/ERRα control Vegf expression independently of hypoxia signaling via the hypoxia inducible factor (HIF) 1α (49), hypoxia increases PGC1α gene expression (49,53) and the Pgc1α-mediated increase in mitochondrial content can indirectly promote cellular hypoxia due to increased oxygen consumption (54).…”

Section: Exercise-induced Changes In Metabolism Of Skeletal Muscle Cementioning

confidence: 99%

Metabolic regulation of exercise-induced angiogenesis

Gorski

Bock

2019

Vascular Biology

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Skeletal muscle relies on an ingenious network of blood vessels, which ensures optimal oxygen and nutrient supply. An increase in muscle vascularization is an early adaptive event to exercise training, but the cellular and molecular mechanisms underlying exercise-induced blood vessel formation are not completely clear. In this review, we provide a concise overview on how exercise-induced alterations in muscle metabolism can evoke metabolic changes in endothelial cells (ECs) that drive muscle angiogenesis. In skeletal muscle, angiogenesis can occur via sprouting and splitting angiogenesis and is dependent on vascular endothelial growth factor (VEGF) signaling. In the resting muscle, VEGF levels are controlled by the estrogen-related receptor γ (ERRγ). Upon exercise, the transcriptional coactivator peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC1α) orchestrates several adaptations to endurance exercise within muscle fibers and simultaneously promotes transcriptional activation of Vegf expression and increased muscle capillary density. While ECs are highly glycolytic and change their metabolism during sprouting angiogenesis in development and disease, a similar role for EC metabolism in exercise-induced angiogenesis in skeletal muscle remains to be elucidated. Nonetheless, recent studies have illustrated the importance of endothelial hydrogen sulfide and sirtuin 1 (SIRT1) activity for exercise-induced angiogenesis, suggesting that EC metabolic reprogramming may be fundamental in this process. We hypothesize that the exercise-induced angiogenic response can also be modulated by metabolic crosstalk between muscle and the endothelium. Defining the underlying molecular mechanisms responsible for skeletal muscle angiogenesis in response to exercise will yield valuable insight into metabolic regulation as well as the determinants of exercise performance.

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ERRγ Promotes Angiogenesis, Mitochondrial Biogenesis, and Oxidative Remodeling in PGC1α/β-Deficient Muscle

Cited by 61 publications

References 32 publications

Undaria pinnatifidaextract feeding increases exercise endurance and skeletal muscle mass by promoting oxidative muscle remodeling in mice

Undaria pinnatifidaextract feeding increases exercise endurance and skeletal muscle mass by promoting oxidative muscle remodeling in mice

Dynamic enhancers control skeletal muscle identity and reprogramming

Metabolic regulation of exercise-induced angiogenesis

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