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This review aims to provide a historical reference of branched-chain amino acid (BCAA) metabolism and provide a link between peripheral and central nervous system (CNS) metabolism of BCAAs. Leucine, isoleucine, and valine (Leu, Ile, and Val) are unlike most other essential amino acids (AA), being transaminated initially in extrahepatic tissues, and requiring interorgan or intertissue shuttling for complete catabolism. Within the periphery, BCAAs are essential AAs and are required for protein synthesis, and are key nitrogen donors in the form of Glu, Gln, and Ala. Leucine is an activator of the mammalian (or mechanistic) target of rapamycin, the master regulator of cell growth and proliferation. The tissue distribution and activity of the catabolic enzymes in the peripheral tissues as well as neurological effects in Maple Syrup Urine Disease (MSUD) show the BCAAs have a role in the CNS. Interestingly, there are significant differences between murine and human CNS enzyme distribution and activities. In the CNS, BCAAs have roles in neurotransmitter synthesis, protein synthesis, food intake regulation, and are implicated in diseases. MSUD is the most prolific disease associated with BCAA metabolism, affecting the branched-chain α-keto acid dehydrogenase complex (BCKDC). Mutations in the branched-chain aminotransferases (BCATs) and the kinase for BCKDC also result in neurological dysfunction. However, there are many questions of BCAA metabolism in the CNS (as well as the periphery) that remain elusive. We discuss areas of BCAA and BCKA metabolism that have yet to be researched adequately.

Branched-chain amino acid transaminase 1, the enzyme that initiates the catabolism of branched-chain amino acids, is involved in glioma pathogenesis, making it a potential therapeutic target. Here we show that glioblastoma express high levels of branched-chain amino acid transaminase 1 (BCAT1), the enzyme that initiates the catabolism of branched-chain amino acids (BCAAs). Expression of BCAT1 was exclusive to tumors carrying wild-type isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and was highly correlated with methylation patterns in the BCAT1 promoter region. BCAT1 expression was dependent on the concentration of α-ketoglutarate substrate in glioma cell lines and could be suppressed by ectopic overexpression of mutant IDH1 in immortalized human astrocytes, providing a link between IDH1 function and BCAT1 expression. Suppression of BCAT1 in glioma cell lines blocked the excretion of glutamate and led to reduced proliferation and invasiveness in vitro , as well as significant decreases in tumor growth in a glioblastoma xenograft model. These findings suggest a central role for BCAT1 in glioma pathogenesis, making BCAT1 and BCAA metabolism attractive targets for the development of targeted therapeutic approaches to treat patients with glioblastoma.

BackgroundThe mitochondrial branched-chain aminotransferase (BCATm) is a recently discovered cancer marker with a poorly defined role in tumour progression.MethodsTo understand how a loss of function of BCATm affects cancer, the global knockout mouse BCATmKO was challenged with EL-4 lymphoma under different diet compositions with varying amounts of branched-chain amino acids (BCAAs). Next, the growth and metabolism of EL-4 cells were studied in the presence of different leucine concentrations in the growth medium.ResultsBCATmKO mice experienced delayed tumour growth when fed standard rodent chow or a normal BCAA diet. Tumour suppression correlated with 37.6- and 18.9-fold increases in plasma and tumour BCAAs, 37.5% and 30.4% decreases in tumour glutamine and alanine, and a 3.5-fold increase in the phosphorylation of tumour AMPK in BCATmKO mice on standard rodent chow. Similar results were obtained with a normal but not with a choice BCAA diet.ConclusionsGlobal deletion of BCATm caused a dramatic build-up of BCAAs, which could not be utilised for energy or amino acid synthesis, ultimately delaying the growth of lymphoma tumours. Furthermore, physiological, but not high, leucine concentrations promoted the growth of EL-4 cells. BCATm and BCAA metabolism were identified as attractive targets for anti-lymphoma therapy.

Alzheimer’s disease (AD) develops along a continuum that spans years prior to diagnosis. Decreased muscle function and mitochondrial respiration occur years earlier in those that develop AD; however, it is unknown what causes these peripheral phenotypes in a disease of the brain. Exercise promotes muscle, mitochondria, and cognitive health and is proposed to be a potential therapeutic for AD, but no study has investigated how skeletal muscle adapts to exercise training in an AD-like context. Utilizing 5xFAD mice, an AD model that develops ad-like pathology and cognitive impairments around 6 mo of age, we examined in vivo neuromuscular function and exercise adapations (mitochondrial respiration and RNA sequencing) before the manifestation of overt cognitive impairment. We found 5xFAD mice develop neuromuscular dysfunction beginning as early as 4 mo of age, characterized by impaired nerve-stimulated muscle torque production and compound nerve action potential of the sciatic nerve. Furthermore, skeletal muscle in 5xFAD mice had altered, sex-dependent, adaptive responses (mitochondrial respiration and gene expression) to exercise training in the absence of overt cognitive impairment. Changes in peripheral systems, specifically neural communication to skeletal muscle, may be harbingers for AD and have implications for lifestyle interventions, like exercise, in AD. Graphical Abstract Graphical Abstract Integrated model for the development of neuromuscular dysfunction in the AD-like pathology of 5xFAD mice. (A) At 3 mo of age, nerve-stimulated muscle function is normal across genotypes and sexes. (B) By as early as 4 mo of age, nerve-stimulated muscle function declines, and (C) corresponds to impaired sciatic nerve function in 5xFAD mice. Peripheral neuromuscular dysfunction (D) corresponds to an altered mitochondrial and transcriptional response of skeletal muscle to exercise training. (E) These peripheral phenotypes of the early AD-like pathology of 5xFAD mice were present in the absence of overt cognitive decline, particularly in male mice. Created in Biorender.

Metabolic flexibility, the capacity to adapt fuel utilization in response to nutrient availability, is essential for maintaining energy homeostasis and preventing metabolic disease. Here, we investigate the role of Ulk1 phosphorylation at serine 555 (S555), a site regulated by AMPK, in coordinating metabolic switching following short-term caloric restriction and fasting. Using Ulk1(S555A) global knock-in mice, we show loss of S555 phosphorylation impairs glucose oxidation in skeletal muscle and liver during short-term CR, despite improved glucose tolerance. Metabolomic, transcriptomic, and mitochondrial respiration analyses suggest a compensatory reliance on autophagy-derived amino acids in Ulk1(S555A) mice. These findings suggest Ulk1(S555) phosphorylation as a critical regulatory event linking nutrient stress to substrate switching. This work highlights an underappreciated role of Ulk1 in maintaining metabolic flexibility, with implications for metabolic dysfunction.