A metabolic basis for motor deficits in mice lacking BCKDK

Branched-chain α-amino acids (BCAAs) support protein synthesis and their oxidation is restrained by branched-chain α-keto acid dehydrogenase kinase (BCKDK). We previously observed that in the brains of Bckdk knockout (KO) mice, BCAAs fall while glutamate is preserved and other amino acids rise. We asked why this profile emerges and how it affects skeletal muscle versus brain during nutrient stress. Motor behavior, protein synthesis and nutrient signaling were compared in the skeletal muscle and brains of wildtype (WT) and Bckdk KO male mice. In addition, nitrogen delivery into brain from BCAAs was assessed using stable isotope tracing and mass spectrometry imaging. Bckdk KO showed normal grip strength but poor beam traversal and reduced wheel running during protein restriction. In skeletal muscle, leucine or protein-feeding stimulated and fasting suppressed mechanistic target of rapamycin complex 1 (mTORC1) signaling in both genotypes. Fasting reduced muscle protein synthesis in both strains without activating the integrated-stress response (ISR). In contrast, Bckdk KO brains exhibited ISR activation during fasting, and up-regulation of Atf4 and its target genes, including Slc7a5 mRNA. Tracer studies revealed lower serum [¹⁵N]-BCAA enrichment and diminished incorporation of BCAA-derived nitrogen into brain glutamate in Bckdk KO mice, despite unchanged total glutamate. Thus, in the non-growing adult constitutive BCKDH activation limits BCAA-derived nitrogen delivery to brain and alters AA transporters as part of an adaptive ISR during nutrient scarcity. This creates a vulnerability in brain not observed in skeletal muscle. These data provide a metabolic basis for poor motor performance in Bckdk KO mice.