Disruption of BCAA metabolism in mice impairs exercise metabolism and endurance

She, Pengxiang; Zhou, Yingsheng; Zhang, Zhiyou; Griffin, Kathleen; Gowda, Kavitha; Lynch, Christopher J.

doi:10.1152/japplphysiol.01248.2009

Cited by 61 publications

(71 citation statements)

References 44 publications

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“…Compared with BCATm ϩ/ϩ mice, whereas basal fasting plasma glucose and insulin concentrations did not differ, plasma insulin concentrations at 3, 4.5, and 6 h of refeeding were decreased more than by half in BCATm Ϫ/Ϫ mice, and plasma glucose concentration at 1 h of refeeding was markedly lowered in these animals. Additionally, after 3 h of refeeding, glycogen contents in liver (data not shown) and skeletal muscle (38) were higher in BCATm Ϫ/Ϫ than BCATm ϩ/ϩ mice. These data suggest improved insulin sensitivity and glucose tolerance in mice without BCATm as reported previously (26) and much lower insulin secretion in response to refeeding in these mice.…”

Section: Effects Of Bcatm Disruption On Plasma Glucose and Insulinmentioning

confidence: 82%

Transamination Is Required for α-Ketoisocaproate but Not Leucine to Stimulate Insulin Secretion*

Zhou

Jetton

Goshorn

et al. 2010

Journal of Biological Chemistry

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It remains unclear how ␣-ketoisocaproate (KIC) and leucine are metabolized to stimulate insulin secretion. Mitochondrial BCATm (branched-chain aminotransferase) catalyzes reversible transamination of leucine and ␣-ketoglutarate to KIC and glutamate, the first step of leucine catabolism. We investigated the biochemical mechanisms of KIC and leucine-stimulated insulin secretion (KICSIS and LSIS, respectively) using Although leucine oxidation and KIC transamination were blocked in BCATm ؊/؊ islets, KIC oxidation was unaltered.These data indicate that KICSIS requires transamination of KIC and glutamate to leucine and ␣-ketoglutarate, respectively. LSIS does not require leucine catabolism and may be through leucine activation of glutamate dehydrogenase. Thus, KICSIS and LSIS occur by enhancing the metabolism of glutamine/glutamate to ␣-ketoglutarate, which, in turn, is metabolized to produce the intracellular signals such as ATP and NADPH for insulin secretion.To maintain glucose homeostasis in response to a meal, insulin secretion is precisely stimulated by nutrients such as glucose, amino acids, and free fatty acids as well as incretin hormones such as glucagon-like peptide-1. Nutrients are thought to stimulate insulin secretion through metabolic secretion coupling to generate metabolic signals, i.e. second messengers or coupling factors. Extensive research has been conducted to determine how nutrients are metabolized to generate these coupling factors, e.g. ATP and NADPH. Although leucine and ␣-ketoisocaproate (KIC) 3 are potent insulin secretagogues (1), the underlying mechanisms of leucine and KIC-stimulated insulin secretion (LSIS and KICSIS, respectively) remain elusive. A key question is whether their oxidative decarboxylation is required for induction of insulin secretion.

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Section: Effects Of Bcatm Disruption On Plasma Glucose and Insulinmentioning

confidence: 82%

Transamination Is Required for α-Ketoisocaproate but Not Leucine to Stimulate Insulin Secretion*

Zhou

Jetton

Goshorn

et al. 2010

Journal of Biological Chemistry

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“…In contrast to the prevailing view that these mice might exhibit metabolic syndrome (62,63), they instead exhibited decreased adiposity and body weight and resistance to diet-induced obesity, even though they ate more food than their wild-type counterparts. In addition, BCATm KO mice exhibited 33% reductions in their plasma glucose levels, a ϳ50% reduction in glucose tolerance test (GTT) areas under the curve along with ϳ50% reductions in plasma insulin during the GTT and improved insulin sensitivity, but not maximal insulin action (76,79). However, these mice also had reduced exercise tolerance (76).…”

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confidence: 99%

“…In addition, BCATm KO mice exhibited 33% reductions in their plasma glucose levels, a ϳ50% reduction in glucose tolerance test (GTT) areas under the curve along with ϳ50% reductions in plasma insulin during the GTT and improved insulin sensitivity, but not maximal insulin action (76,79). However, these mice also had reduced exercise tolerance (76). The lower fasting glucose and exercise intolerance might be related in part to the important role of BCAA transamination in gluconeogenic amino acid production that is likely important during exercise.…”

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confidence: 99%

“…While BCATm skeletal muscle exhibits increased protein synthesis and degradation, other tissues such as heart, kidney, and spleen appear to be protected as might occur in starvation (61). Finally, BCATm KO mice were exercise intolerant (76). This was largely postulated to be associated with their low circulating substrates and energy reserves, interruption of the muscle malate-aspartate cycle, along with the increased lactate-topyruvate ratio and ammonia in skeletal muscle observed after exercise.…”

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confidence: 99%

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Global deletion ofBCATmincreases expression of skeletal muscle genes associated with protein turnover

Lynch

Kimball

et al. 2015

Physiological Genomics

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Lynch CJ, Kimball SR, Xu Y, Salzberg AC, Kawasawa YI. Global deletion of BCATm increases expression of skeletal muscle genes associated with protein turnover. Physiol Genomics 47: 569-580, 2015. First published September 8, 2015 doi:10.1152/physiolgenomics.00055.2015.-Consumption of a protein-containing meal by a fasted animal promotes protein accretion in skeletal muscle, in part through leucine stimulation of protein synthesis and indirectly through repression of protein degradation mediated by its metabolite, ␣-ketoisocaproate. Mice lacking the mitochondrial branched-chain aminotransferase (BCATm/Bcat2), which interconverts leucine and ␣-ketoisocaproate, exhibit elevated protein turnover. Here, the transcriptomes of gastrocnemius muscle from BCATm knockout (KO) and wildtype mice were compared by next-generation RNA sequencing (RNA-Seq) to identify potential adaptations associated with their persistently altered nutrient signaling. Statistically significant changes in the abundance of 1,486/ϳ39,010 genes were identified. Bioinformatics analysis of the RNA-Seq data indicated that pathways involved in protein synthesis [eukaryotic initiation factor (eIF)-2, mammalian target of rapamycin, eIF4, and p70S6K pathways including 40S and 60S ribosomal proteins], protein breakdown (e.g., ubiquitin mediated), and muscle degeneration (apoptosis, atrophy, myopathy, and cell death) were upregulated. Also in agreement with our previous observations, the abundance of mRNAs associated with reduced body size, glycemia, plasma insulin, and lipid signaling pathways was altered in BCATm KO mice. Consistently, genes encoding anaerobic and/or oxidative metabolism of carbohydrate, fatty acids, and branched chain amino acids were modestly but systematically reduced. Although there was no indication that muscle fiber type was different between KO and wild-type mice, a difference in the abundance of mRNAs associated with a muscular dystrophy phenotype was observed, consistent with the published exercise intolerance of these mice. The results suggest transcriptional adaptations occur in BCATm KO mice that along with altered nutrient signaling may contribute to their previously reported protein turnover, metabolic and exercise phenotypes.

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“…In the present study, exercise decreased BCAA in db mice more than food restriction in db mice. In db mice, branched-chain a-keto acids such as isovaleric acid showed lower excretion in urine [32], indicating the slow degradation and transport of BCAA in WAT and SM, which are thought to play a role in BCAA metabolism [26,27,33]. The gene expressions of BCAT2, SLC3A2, and SLC7A5, the responsible genes in BCAA degradation and transport, were not altered under exercise conditions in our models, except BCAT2 in SM (Fig.…”

Section: Discussionmentioning

confidence: 71%

Voluntary exercise under a food restriction condition decreases blood branched-chain amino acid levels, in addition to improvement of glucose and lipid metabolism, in db mice, animal model of type 2 diabetes

Marchianti

Emi

Ushikai

et al. 2014

Environ Health Prev Med

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Objectives Exercise is effective for preventing the onset and development of type 2 diabetes mellitus (T2DM) in human cases; however, the effect of exercise on the pathophysiology using animal models of T2DM has not been fully evaluated. Methods We applied voluntary exercise under pair-fed (P) conditions in db mice, an animal model of T2DM. Exercising (Ex) and sedentary (Se) mice were placed in a cage, equipped with a free or locked running wheel, for 4 weeks, respectively. The amount of food consumed by ad libitum-fed wild-type mice under the Se condition (ad-WT) was supplied to all mice, except ad libitum db mice (ad-db). Blood parameters and expression of the genes involved in nutrient metabolism were analyzed. Results PEx-db (pair-fed and exercising) mice showed significantly lower HbA1c, body weight and liver weight than PSe-db and ad-db mice. Decreased hepatic triglycerides in PEx-db mice corresponded to a lower expression of lipogenic enzyme genes in the liver. Moreover, PEx-db mice showed significantly lower plasma branched-chain amino acids (BCAA), arginine, proline, and tyrosine, in addition to increased skeletal muscle (SM) weight, than PSe-db and ad-db mice, in spite of little influence on the expression of the BCAA transaminase gene, in SM and WAT. Conclusion We found that exercise under a food restriction condition decreases several amino acids, including BCAA, and may improve insulin sensitivity more than mere food restriction. We propose that the decreased concentration of blood amino acids may be a valuable marker evaluating the effects of exercise on diabetic conditions.

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Disruption of BCAA metabolism in mice impairs exercise metabolism and endurance

Cited by 61 publications

References 44 publications

Transamination Is Required for α-Ketoisocaproate but Not Leucine to Stimulate Insulin Secretion*

Transamination Is Required for α-Ketoisocaproate but Not Leucine to Stimulate Insulin Secretion*

Global deletion ofBCATmincreases expression of skeletal muscle genes associated with protein turnover

Voluntary exercise under a food restriction condition decreases blood branched-chain amino acid levels, in addition to improvement of glucose and lipid metabolism, in db mice, animal model of type 2 diabetes

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