GCN2 is Essential for the Survival of Mice Born Deficient in Branched‐Chain alpha‐Ketoacid Dehydrogenase Kinase (BDK).

The branched‐chain alpha‐keto acid dehydrogenase enzyme complex catalyzes the irreversible catabolism of the branched‐chain amino acids (BCAA). Phosphorylation of the complex by its kinase, BDK, inhibits BCAA oxidation. Mice lacking BDK (BDK −/− ) demonstrate decreased BCAA levels, impaired somatic and skeletal muscle growth, and neurological abnormalities. Dietary deficiency of BCAA increases phosphorylation of the translation factor, eIF2, by the protein kinase, GCN2, leading to activation of an amino acid stress response that serves to promote cell adaptation. To understand if GCN2 is involved in the development of the BDK −/− phenotype, GCN2 −/− and BDK −/− mice were bred to produce GCN2‐BDK double null mice (GB) alongside wild‐type and single null littermates (all on C57BL/6J background). At d1 postpartum, GB pups are indistinguishable from littermates in size, weight, blood glucose and liver glycogen. However, by d7 GB pups stop gaining weight and blood glucose is reduced 44%. Between d7‐d14, GB pups fail to right themselves, demonstrate splaying of the limbs, uncontrollable shaking and weight loss. Despite cross‐fostering at birth and daily provision of glucose and BCAA, GB pups mice become progressively wasted and neurologically unresponsive, expiring by d15. All GB body tissues collected between d11‐d14 are significantly reduced in size, except brain, which is increased 33% as compared to non‐GB littermates. These data demonstrate that GCN2 is critical for surviving BCAA deficiency during early postnatal life.