A metabolic basis for motor deficits in mice lacking BCKDK

Area of Science:

• Biochemistry
• Neuroscience
• Metabolic Regulation

Background:

• Branched-chain α-amino acids (BCAAs) are crucial for protein synthesis.
• Branched-chain α-keto acid dehydrogenase kinase (BCKDK) restrains BCAA oxidation.
• Previous studies in Bckdk knockout (KO) mice showed altered amino acid profiles in the brain.

Purpose of the Study:

• To investigate the reasons behind altered brain amino acid profiles in Bckdk KO mice.
• To compare the effects of nutrient stress on skeletal muscle and brain in Bckdk KO versus wildtype (WT) mice.
• To assess BCAA-derived nitrogen delivery into the brain.

Main Methods:

• Comparative analysis of motor behavior, protein synthesis, and nutrient signaling in skeletal muscle and brain of WT and Bckdk KO mice.
• Stable isotope tracing and mass spectrometry imaging to track nitrogen delivery from BCAAs to the brain.
• Assessment of integrated-stress response (ISR) activation and specific gene expression (Atf4, Slc7a5).

Main Results:

• Bckdk KO mice exhibited normal grip strength but impaired motor behavior (beam traversal, wheel running) during protein restriction.
• Skeletal muscle mTORC1 signaling responded similarly to feeding and fasting in both genotypes.
• Bckdk KO brains showed ISR activation, increased Atf4 and Slc7a5 mRNA during fasting, with reduced BCAA-derived nitrogen incorporation into brain glutamate.
• Despite unchanged total brain glutamate, Bckdk KO mice had lower serum [15N]-BCAA enrichment.

Conclusions:

• Constitutive BCKDH activation in adult mice limits BCAA-derived nitrogen delivery to the brain under nutrient scarcity.
• This limitation triggers an adaptive ISR in the brain, altering amino acid transporters.
• The observed brain vulnerability in Bckdk KO mice during nutrient stress provides a metabolic basis for their poor motor performance.