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Estrogen-related receptor gamma is a key regulator of muscle mitochondrial activity and oxidative capacity.

Rangwala SM, Wang X, Calvo JA, Lindsley L, Zhang Y, Deyneko G, Beaulieu V, Gao J, Turner G, Markovits J - J. Biol. Chem. (2010)

Bottom Line: Furthermore, peak oxidative capacity was higher in the transgenics as compared with control littermates.Our data indicate that ERRgamma plays an important role in causing a shift toward slow twitch muscle type and, concomitantly, a greater capacity for endurance exercise.Thus, the activation of this nuclear receptor provides a potential node for therapeutic intervention for diseases such as obesity, which is associated with reduced oxidative metabolism and a lower type I fiber content in skeletal muscle.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA. shamina.rangwala@novartis.com

ABSTRACT
Estrogen-related receptor gamma (ERRgamma) regulates the perinatal switch to oxidative metabolism in the myocardium. We wanted to understand the significance of induction of ERRgamma expression in skeletal muscle by exercise. Muscle-specific VP16ERRgamma transgenic mice demonstrated an increase in exercise capacity, mitochondrial enzyme activity, and enlarged mitochondria despite lower muscle weights. Furthermore, peak oxidative capacity was higher in the transgenics as compared with control littermates. In contrast, mice lacking one copy of ERRgamma exhibited decreased exercise capacity and muscle mitochondrial function. Interestingly, we observed that increased ERRgamma in muscle generates a gene expression profile that closely overlays that of red oxidative fiber-type muscle. We further demonstrated that a small molecule agonist of ERRbeta/gamma can increase mitochondrial function in mouse myotubes. Our data indicate that ERRgamma plays an important role in causing a shift toward slow twitch muscle type and, concomitantly, a greater capacity for endurance exercise. Thus, the activation of this nuclear receptor provides a potential node for therapeutic intervention for diseases such as obesity, which is associated with reduced oxidative metabolism and a lower type I fiber content in skeletal muscle.

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Gene expression profile of ERRγ transgenic muscle is similar to that of type I oxidative muscle. A, heat map representing the coordinate gene expression pathways in tibialis anterior (TA) and soleus (Sol) (left panel) and wild type (WT) and VP16ERRγ transgenic (right panel) gastrocnemius muscle. Each individual column within the heat map represents a single mouse subject (n = 3 each for the soleus and tibialis anterior, n = 6 for WT and 7 for TG mice). The expression values are standardized within the data sets. Red color means up-regulation; green is down-regulation, and black is no change. The color scale is represented in Fig. 5A. The significantly over-represented GO terms by each group of genes is marked on the right. The p values used to determine significance for the individual genes are as follows: p < 0.01 for TG versus WT and p < 0.05 for soleus versus tibialis anterior. B, table represents the number of genes significantly changed in both datasets. The p value of Fisher's exact test is 1.47e-170 for the  hypothesis that the genes regulated by VP16ERRγ are unrelated to those differentially expressed between soleus and tibialis anterior (TA) muscle.
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Figure 4: Gene expression profile of ERRγ transgenic muscle is similar to that of type I oxidative muscle. A, heat map representing the coordinate gene expression pathways in tibialis anterior (TA) and soleus (Sol) (left panel) and wild type (WT) and VP16ERRγ transgenic (right panel) gastrocnemius muscle. Each individual column within the heat map represents a single mouse subject (n = 3 each for the soleus and tibialis anterior, n = 6 for WT and 7 for TG mice). The expression values are standardized within the data sets. Red color means up-regulation; green is down-regulation, and black is no change. The color scale is represented in Fig. 5A. The significantly over-represented GO terms by each group of genes is marked on the right. The p values used to determine significance for the individual genes are as follows: p < 0.01 for TG versus WT and p < 0.05 for soleus versus tibialis anterior. B, table represents the number of genes significantly changed in both datasets. The p value of Fisher's exact test is 1.47e-170 for the hypothesis that the genes regulated by VP16ERRγ are unrelated to those differentially expressed between soleus and tibialis anterior (TA) muscle.

Mentions: We analyzed our microarray data in context of the gene signatures observed in two distinct muscle fiber types (Fig. 4A, left panel) that were generated based on a published data set described for tibialis anterior muscle, a representative of type II fast twitch glycolytic muscle, and soleus muscle, which is a slow type I fiber oxidative muscle NCBI GEO accession number GSE10347) (31). Classically, the definition of the skeletal muscle fiber type is based on MHC profile distribution, as well as determination of ATPase activity (32). Interestingly, we observed that the majority of gene signature up-regulated in soleus muscle is also induced in the ERRγ transgenic mice; conversely, the gene pathways decreased in soleus but increased in the tibialis are decreased in the ERRγ transgenic muscle (Fig. 4A, right panel). Gene pathways over-represented in the soleus and transgenic muscle were those of fatty acid oxidation, oxidoreductases, muscle fiber type, angiogenesis, and extracellular matrix components. Gene pathways representing glucose metabolism, fast twitch muscle, and calmodulin binding were lower in soleus as compared with the tibialis muscle and were similarly lower in the transgenic muscle as compared with the wild type. Statistical analysis of this cross-comparison yielded a high a degree of significance (Fig. 4B). Thus, we can closely overlay the molecular genetic signature of ERRγ onto that of a pure oxidative muscle.


Estrogen-related receptor gamma is a key regulator of muscle mitochondrial activity and oxidative capacity.

Rangwala SM, Wang X, Calvo JA, Lindsley L, Zhang Y, Deyneko G, Beaulieu V, Gao J, Turner G, Markovits J - J. Biol. Chem. (2010)

Gene expression profile of ERRγ transgenic muscle is similar to that of type I oxidative muscle. A, heat map representing the coordinate gene expression pathways in tibialis anterior (TA) and soleus (Sol) (left panel) and wild type (WT) and VP16ERRγ transgenic (right panel) gastrocnemius muscle. Each individual column within the heat map represents a single mouse subject (n = 3 each for the soleus and tibialis anterior, n = 6 for WT and 7 for TG mice). The expression values are standardized within the data sets. Red color means up-regulation; green is down-regulation, and black is no change. The color scale is represented in Fig. 5A. The significantly over-represented GO terms by each group of genes is marked on the right. The p values used to determine significance for the individual genes are as follows: p < 0.01 for TG versus WT and p < 0.05 for soleus versus tibialis anterior. B, table represents the number of genes significantly changed in both datasets. The p value of Fisher's exact test is 1.47e-170 for the  hypothesis that the genes regulated by VP16ERRγ are unrelated to those differentially expressed between soleus and tibialis anterior (TA) muscle.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 4: Gene expression profile of ERRγ transgenic muscle is similar to that of type I oxidative muscle. A, heat map representing the coordinate gene expression pathways in tibialis anterior (TA) and soleus (Sol) (left panel) and wild type (WT) and VP16ERRγ transgenic (right panel) gastrocnemius muscle. Each individual column within the heat map represents a single mouse subject (n = 3 each for the soleus and tibialis anterior, n = 6 for WT and 7 for TG mice). The expression values are standardized within the data sets. Red color means up-regulation; green is down-regulation, and black is no change. The color scale is represented in Fig. 5A. The significantly over-represented GO terms by each group of genes is marked on the right. The p values used to determine significance for the individual genes are as follows: p < 0.01 for TG versus WT and p < 0.05 for soleus versus tibialis anterior. B, table represents the number of genes significantly changed in both datasets. The p value of Fisher's exact test is 1.47e-170 for the hypothesis that the genes regulated by VP16ERRγ are unrelated to those differentially expressed between soleus and tibialis anterior (TA) muscle.
Mentions: We analyzed our microarray data in context of the gene signatures observed in two distinct muscle fiber types (Fig. 4A, left panel) that were generated based on a published data set described for tibialis anterior muscle, a representative of type II fast twitch glycolytic muscle, and soleus muscle, which is a slow type I fiber oxidative muscle NCBI GEO accession number GSE10347) (31). Classically, the definition of the skeletal muscle fiber type is based on MHC profile distribution, as well as determination of ATPase activity (32). Interestingly, we observed that the majority of gene signature up-regulated in soleus muscle is also induced in the ERRγ transgenic mice; conversely, the gene pathways decreased in soleus but increased in the tibialis are decreased in the ERRγ transgenic muscle (Fig. 4A, right panel). Gene pathways over-represented in the soleus and transgenic muscle were those of fatty acid oxidation, oxidoreductases, muscle fiber type, angiogenesis, and extracellular matrix components. Gene pathways representing glucose metabolism, fast twitch muscle, and calmodulin binding were lower in soleus as compared with the tibialis muscle and were similarly lower in the transgenic muscle as compared with the wild type. Statistical analysis of this cross-comparison yielded a high a degree of significance (Fig. 4B). Thus, we can closely overlay the molecular genetic signature of ERRγ onto that of a pure oxidative muscle.

Bottom Line: Furthermore, peak oxidative capacity was higher in the transgenics as compared with control littermates.Our data indicate that ERRgamma plays an important role in causing a shift toward slow twitch muscle type and, concomitantly, a greater capacity for endurance exercise.Thus, the activation of this nuclear receptor provides a potential node for therapeutic intervention for diseases such as obesity, which is associated with reduced oxidative metabolism and a lower type I fiber content in skeletal muscle.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA. shamina.rangwala@novartis.com

ABSTRACT
Estrogen-related receptor gamma (ERRgamma) regulates the perinatal switch to oxidative metabolism in the myocardium. We wanted to understand the significance of induction of ERRgamma expression in skeletal muscle by exercise. Muscle-specific VP16ERRgamma transgenic mice demonstrated an increase in exercise capacity, mitochondrial enzyme activity, and enlarged mitochondria despite lower muscle weights. Furthermore, peak oxidative capacity was higher in the transgenics as compared with control littermates. In contrast, mice lacking one copy of ERRgamma exhibited decreased exercise capacity and muscle mitochondrial function. Interestingly, we observed that increased ERRgamma in muscle generates a gene expression profile that closely overlays that of red oxidative fiber-type muscle. We further demonstrated that a small molecule agonist of ERRbeta/gamma can increase mitochondrial function in mouse myotubes. Our data indicate that ERRgamma plays an important role in causing a shift toward slow twitch muscle type and, concomitantly, a greater capacity for endurance exercise. Thus, the activation of this nuclear receptor provides a potential node for therapeutic intervention for diseases such as obesity, which is associated with reduced oxidative metabolism and a lower type I fiber content in skeletal muscle.

Show MeSH
Related in: MedlinePlus