Expression data from quadriceps muscle of WT and ERRgamma transgenic mice

We show that the orphan nuclear receptor ERRg is expressed at high levels in type I muscle and when transgenically expressed in anaerobic type II muscles (ERRGO mice) or cultured cells, powerfully regulates VEGF expression, angiogenesis and vascular supply in absence of exercise. ERRGO mice show increased expression of genes promoting fat metabolism, mitochondrial respiration and type I fiber specification. In parallel, the type II muscle in ERRGO mice display an activated angiogenic program marked by myofibrillar induction and secretion of pro-angiogenic factors, frank neo-vascularization and a 100% increase in running endurance. Surprisingly, the induction of VEGF and type I muscle properties by ERRg does not involve the transcriptional co-activator PGC1a. Instead, ERRg genetically activates the energy sensor AMPK which is typically inactive in absence of exercise. Therefore, ERRg and AMPK, known regulators of mitochondrial function and metabolism, together control a novel angiogenic pathway that anatomically synchronizes vascular arborization to oxidative metabolism revealing an exercise-independent mechanism for matching supply and demand.

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