| Estrogen-related receptor α (ERRα/NR3B1) is an orphan member of the nuclear receptor superfamily within the ERR subfamily, where it functions as a constitutively active transcription factor that integrates coactivator signals with control of cellular energy metabolism and differentiation programs in high-demand tissues such as heart and skeletal muscle. The receptor contains the canonical modular nuclear receptor architecture with an N‑terminal activation domain, a central zinc finger DNA-binding domain that recognizes extended estrogen response element–related motifs, and a C‑terminal ligand-binding domain whose AF‑2 surface provides high-affinity docking sites for peroxisome proliferator-activated receptor γ coactivator-1α (PGC‑1α) and PGC‑1β, forming a coactivator–receptor complex that drives transcriptional output from metabolic gene promoters. ERRα activated by PGC‑1α coactivator complexes binds regulatory regions of genes involved in fatty acid β‑oxidation, oxidative phosphorylation, tricarboxylic acid cycle function, and mitochondrial biogenesis, where it coordinates expression of enzymes of substrate uptake and oxidation with mitochondrial respiratory chain components, thereby setting the oxidative metabolic capacity of cardiac and skeletal muscle fibers under physiological and stress conditions. In skeletal myocytes, ERRα expression rises early during myogenic differentiation in parallel with PGC‑1α, and gain‑ and loss‑of‑function analyses show that ERRα activity accelerates myotube formation and sarcomeric organization, while pharmacologic antagonism or genetic deletion delays differentiation and reduces mitochondrial content without broadly suppressing metabolic gene expression. ERRα modulates ERK/MAP kinase signaling: ERRα–PGC‑1α complexes occupy the proximal regulatory region of the Dusp1 gene encoding MAP kinase phosphatase‑1 (MKP‑1), upregulate its transcription at the onset of myogenesis, and thereby promote ERK dephosphorylation, whereas ERRα deficiency or antagonist treatment blunts Dusp1 induction, sustains ERK activation, and interferes with timely myotube maturation. |
