BCATm deficiency ameliorates endotoxin-induced decrease in muscle protein synthesis and improves survival in septic mice

Lang, Charles H.; Lynch, Christopher J.; Vary, Thomas C.

doi:10.1152/ajpregu.00297.2010

Cited by 33 publications

(31 citation statements)

References 58 publications

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“…Protein synthesis was determined using the flooding-dose technique, exactly as described (28,29). Mice were injected intraperitoneally with [ 3 H]-L-phenylalanine (150 mmol/L, 30 μCi/mL, 1 mL/100 g body wt), and blood was collected 15 min later for determining the plasma phenylalanine concentration and radioactivity.…”

Section: In Vivo Protein Synthesismentioning

confidence: 99%

Deptor Knockdown Enhances mTOR Activity and Protein Synthesis in Myocytes and Ameliorates Disuse Muscle Atrophy

Kazi

Hong-Brown

Lang

et al. 2011

Mol Med

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Deptor is an mTOR binding protein that affects cell metabolism. We hypothesized that knockdown (KD) of Deptor in C2C12 myocytes will increase protein synthesis via stimulating mTOR-S6K1 signaling. Deptor KD was achieved using lentiviral particles containing short hairpin (sh)RNA targeting the mouse Deptor mRNA sequence, and control cells were transfected with a scrambled control shRNA. KD reduced Deptor mRNA and protein content by 90%, which increased phosphorylation of mTOR kinase substrates, 4E-BP1 and S6K1, and concomitantly increased protein synthesis. Deptor KD myoblasts were both larger in diameter and exhibited an increased mean cell volume. Deptor KD increased the percentage of cells in the S phase, coincident with an increased phosphorylation (S807/S811) of retinoblastoma protein (pRb) that is critical for the G 1 to S phase transition. Deptor KD did not appear to alter basal apoptosis or autophagy, as evidenced by the lack of change for cleaved caspase-3 and light chain (LC)3B, respectively. Deptor KD increased proliferation rate and enhanced myotube formation. Finally, in vivo Deptor KD (~50% reduction) by electroporation into gastrocnemius of C57/BL6 mice did not alter weight or protein synthesis in control muscle. However, Deptor KD prevented atrophy produced by 3 d of hindlimb immobilization, at least in part by increasing protein synthesis. Thus, our data support the hypothesis that Deptor is an important regulator of protein metabolism in myocytes and demonstrate that decreasing Deptor expression in vivo is sufficient to ameliorate muscle atrophy.

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Section: In Vivo Protein Synthesismentioning

confidence: 99%

Deptor Knockdown Enhances mTOR Activity and Protein Synthesis in Myocytes and Ameliorates Disuse Muscle Atrophy

Kazi

Hong-Brown

Lang

et al. 2011

Mol Med

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“…Instead, increased energy expenditure in these mice was postulated to arise from an increased protein turnover (24,74) arising from an increase in mTOR signaling brought about by elevated Leu along with loss of the putative KIC signal to protein degradation postulated originally by Tischler et al (26,81). Moreover, the increase in protein synthesis in these mice helped protect them from endotoxin-induced decrease in muscle protein synthesis and improve their survival during sepsis (48). 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).…”

mentioning

confidence: 97%

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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“…Polymicrobial peritonitis was produced by cecal ligation and puncture (CLP), as described previously (27, 30). Specific pathogen-free male C57Bl/6 mice (8–10 wks of age, ~25 g, Charles River, Wilmington, MA were anesthetized using isoflurane (3% induction +1.5–2% maintenance) (Abbott Laboratories, North Chicago, IL).…”

Section: Methodsmentioning

confidence: 99%

Salutary Effect of Aurintricarboxylic Acid on Endotoxin- and Sepsis-Induced Changes in Muscle Protein Synthesis and Inflammation

Laufenberg

Kazi

Lang

2014

Shock

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Small molecule nonpeptidyl molecules are potentially attractive drug candidates as adjunct therapies in the treatment of sepsis-induced metabolic complications. As such, the current study investigates the use of aurintricarboxylic acid (ATA), which stimulates insulin-like growth factor (IGF)-I receptor and AKT signaling, for its ability to ameliorate the protein metabolic effects of endotoxin (LPS) + interferon (IFN)γ in C2C12 myotubes and sepsis in skeletal muscle. ATA dose- and time-dependently increases mTOR-dependent protein synthesis. Pretreatment with ATA prevents the LPS/IFNγ-induced decrease in protein synthesis at least in part by maintaining mTOR kinase activity, while post-treatment with ATA is able to increase protein synthesis when added up to 6 h after LPS/IFNγ. ATA also reverses the amino acid resistance which is detected in response to nutrient deprivation. Conversely, ATA decreases the basal rate of protein degradation and prevents the LPS/IFNγ-increase in proteolysis, and the latter change is associated reduced atrogin-1 and MuRF1 mRNA. The ability of ATA to antagonize LPS/IFNγ-induced changes in protein metabolism were associated with its ability to prevent the increases in IL-6 and NOS2 and decreases in IGF-I. In vivo studies indicate ATA acutely increases skeletal muscle, but not cardiac, protein synthesis, and attenuates the loss of lean body mass over 5 days. These data suggest ATA and other small molecule agonists of endogenous anabolic hormones may prove beneficial in treating sepsis by decreasing the inflammatory response and improving muscle protein balance.

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BCATm deficiency ameliorates endotoxin-induced decrease in muscle protein synthesis and improves survival in septic mice

Cited by 33 publications

References 58 publications

Deptor Knockdown Enhances mTOR Activity and Protein Synthesis in Myocytes and Ameliorates Disuse Muscle Atrophy

Deptor Knockdown Enhances mTOR Activity and Protein Synthesis in Myocytes and Ameliorates Disuse Muscle Atrophy

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

Salutary Effect of Aurintricarboxylic Acid on Endotoxin- and Sepsis-Induced Changes in Muscle Protein Synthesis and Inflammation

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