Estrogen-related receptor gamma is a key regulator of muscle mitochondrial activity and oxidative capacity.
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.
Rangwala
Shamina M
SM
Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA. shamina.rangwala@novartis.com
Wang
Xiaomei
X
Calvo
Jennifer A
JA
Lindsley
Loren
L
Zhang
Yunyu
Y
Deyneko
Galina
G
Beaulieu
Valerie
V
Gao
Jiaping
J
Turner
Gordon
G
Markovits
Judit
J
D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D020869:Gene Expression Profiling; D006579:Heterozygote; D006834:Hydrazines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D010084:Oxidation-Reduction / Q000187:drug effects; D010805:Physical Conditioning, Animal; D011960:Receptors, Estrogen / Q000819:agonists / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
C490916:Esrrg protein, mouse; C545235:GSK 4716; D006834:Hydrazines; D011960:Receptors, Estrogen