Editors' ChoiceMetabolism

A better workout without PHD3

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Science Signaling  11 Aug 2020:
Vol. 13, Issue 644, eabe2256
DOI: 10.1126/scisignal.abe2256

PHD3 deficiency increases fatty acid oxidation in skeletal muscle and improves endurance exercise performance.

The enzyme ACC2 limits fatty acid oxidation (FAO). During energy stress, such as during exercise, the kinase AMPK phosphorylates Ser222 in ACC2 and inhibits its activity. FAO is increased in acute myeloid leukemia cells, a phenotype linked to reduced hydroxylation of ACC2 by the prolyl hydroxylase PHD3 due to decreased PHD3 abundance. Yoon et al. investigated the interplay between these two posttranslational modifications in the regulation of ACC2 activity in skeletal muscle. AMPK-mediated phosphorylation and PHD3-mediated hydroxylation of Pro450 were inversely correlated, such that ACC2 phosphorylation was high and hydroxylation was low in MEFs cultured in low glucose or in heart and quadriceps muscle from fasted mice. PHD3-mediated hydroxylation of ACC2 was inhibited by AMPK-mediated phosphorylation in cells and in vivo, and the interaction of PHD3 with ACC2 was increased in cells exposed to high glucose compared to that in cells exposed to low glucose. ACC2 phosphorylation was increased and ACC2 hydroxylation was decreased in skeletal muscle from exercised mice. Global or skeletal muscle–specific deficiency in PHD3 increased exercise endurance in mice, and FAO was increased in quadriceps muscles from these mice. Thus, PHD3-mediated hydroxylation of ACC2 suppresses FAO and is inhibited by AMPK-mediated phosphorylation.

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