Skeletal muscle PGC-1α controls whole-body lactate homeostasis through estrogen-related receptor α-dependent activation of LDH B and repression of LDH A

The peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha) controls metabolic adaptations. We now show that PGC-1 alpha in skeletal muscle drives the expression of lactate dehydrogenase (LDH) B in an estrogen-related receptor-alpha-dependent manner. Concomitantly, PGC-1 alpha reduces the expression of LDH A and one of its regulators, the transcription factor myelocytomatosis oncogene. PGC-1 alpha thereby coordinately alters the composition of the LDH complex and prevents the increase in blood lactate during exercise. Our results show how PGC-1 alpha actively coordinates lactate homeostasis and provide a unique molecular explanation for PGC-1 alpha-mediated muscle adaptations to training that ultimately enhance exercise performance and improve metabolic health.