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Amino acid deprivation due to overexpression of UCP1 in skeletal muscle: signalling via FGF-21

ABSTRACT: Recent studies on mouse and human skeletal muscle (SM) demonstrated the important link between mitochondrial function and the cellular metabolic adaptation. To identify key compensatory molecular mechanisms in response to chronic mitochondrial distress, we analyzed mice with ectopic SM respiratory uncoupling in uncoupling protein 1 transgenic (UCP1-TG) mice as model of muscle-specific compromised mitochondrial function. Here we describe a detailed metabolic reprogramming profile associated with mitochondrial perturbations in SM, triggering an increased protein turnover and amino acid metabolism with induced biosynthetic serine/1-carbon/glycine pathway and the longevity-promoting polyamine spermidine as well as the trans-sulfuration pathway. This is related to an induction of NADPH-generating pathways and glutathione metabolism as an adaptive mitohormetic response and defense against increased oxidative stress. Strikingly, consistent muscle retrograde signaling profiles were observed in acute stress states such as muscle cell starvation and lipid overload, muscle regeneration, and heart muscle inflammation, but not in response to exercise. We provide conclusive evidence for a key compensatory stress-signaling network that preserves cellular function, oxidative stress tolerance, and survival during conditions of increased SM mitochondrial distress, a metabolic reprogramming profile so far only demonstrated for cancer cells and heart muscle.-Ost, M., Keipert, S., van Schothorst, E. M., Donner, V., van der Stelt, I., Kipp, A. P., Petzke, K.-J., Jove, M., Pamplona, R., Portero-Otin, M., Keijer, J., and Klaus, S. Muscle mitohormesis promotes cellular survival via serine/glycine pathway flux.

ORGANISM(S): Mus musculus

PROVIDER: GSE45991 | GEO | 2015/02/17

SECONDARY ACCESSION(S): PRJNA196841

REPOSITORIES: GEO

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Project description:Recent studies on mouse and human skeletal muscle (SM) demonstrated the important link between mitochondrial function and the cellular metabolic adaptation. To identify key compensatory molecular mechanisms in response to chronic mitochondrial distress, we analyzed mice with ectopic SM respiratory uncoupling in uncoupling protein 1 transgenic (UCP1-TG) mice as model of muscle-specific compromised mitochondrial function. Here we describe a detailed metabolic reprogramming profile associated with mitochondrial perturbations in SM, triggering an increased protein turnover and amino acid metabolism with induced biosynthetic serine/1-carbon/glycine pathway and the longevity-promoting polyamine spermidine as well as the trans-sulfuration pathway. This is related to an induction of NADPH-generating pathways and glutathione metabolism as an adaptive mitohormetic response and defense against increased oxidative stress. Strikingly, consistent muscle retrograde signaling profiles were observed in acute stress states such as muscle cell starvation and lipid overload, muscle regeneration, and heart muscle inflammation, but not in response to exercise. We provide conclusive evidence for a key compensatory stress-signaling network that preserves cellular function, oxidative stress tolerance, and survival during conditions of increased SM mitochondrial distress, a metabolic reprogramming profile so far only demonstrated for cancer cells and heart muscle.-Ost, M., Keipert, S., van Schothorst, E. M., Donner, V., van der Stelt, I., Kipp, A. P., Petzke, K.-J., Jove, M., Pamplona, R., Portero-Otin, M., Keijer, J., and Klaus, S. Muscle mitohormesis promotes cellular survival via serine/glycine pathway flux. Control C57BL/6J wildtype male mice, aged 12 weeks, are compared to UCP1 transgene littermates fed purified low fat diet (BIOCLAIMS, Hoevenaars et al., Genes and Nutrition 2012) for 12 weeks . At the end, mice were sacrificed, gastrocnemius skeletal muscle was immediately dissected and snap frozen in liquid nitrogen. Total RNA was isolated, quantified and qualified, and subsequently used for global gene expression profiling using Agilent 8x60K microarrays. In total, 6 arrays of individual WT and 7 arrays of individual UCP1-TG samples were normalized, together with samples from the complete SUPERSERIES.

Project description:This is the model described in the article: In silico experimentation with a model of hepatic mitochondrial folate metabolism. H. Frederik Nijhout, Michael C Reed, Shi-Ling Lam, Barry Shane, Jesse F Gregory and Cornelia M Ulrich, Theor Biol Med Model 2006,3:40; PubmedID: 17150100 ; DOI: 10.1186/1742-4682-3-40 ; Abstract: BACKGROUND: In eukaryotes, folate metabolism is compartmentalized and occurs in both the cytosol and the mitochondria. The function of this compartmentalization and the great changes that occur in the mitochondrial compartment during embryonic development and in rapidly growing cancer cells are gradually becoming understood, though many aspects remain puzzling and controversial. APPROACH: We explore the properties of cytosolic and mitochondrial folate metabolism by experimenting with a mathematical model of hepatic one-carbon metabolism. The model is based on known biochemical properties of mitochondrial and cytosolic enzymes. We use the model to study questions about the relative roles of the cytosolic and mitochondrial folate cycles posed in the experimental literature. We investigate: the control of the direction of the mitochondrial and cytosolic serine hydroxymethyltransferase (SHMT) reactions, the role of the mitochondrial bifunctional enzyme, the role of the glycine cleavage system, the effects of variations in serine and glycine inputs, and the effects of methionine and protein loading. CONCLUSION: The model reproduces many experimental findings and gives new insights into the underlying properties of mitochondrial folate metabolism. Particularly interesting is the remarkable stability of formate production in the mitochondria in the face of large changes in serine and glycine input. The model shows that in the presence of the bifunctional enzyme (as in embryonic tissues and cancer cells), the mitochondria primarily support cytosolic purine and pyrimidine synthesis via the export of formate, while in adult tissues the mitochondria produce serine for gluconeogenesis. This model does not reproduce the results in the article completely, but most steady state concentrations are in a range of 10% around the published values. Also parameterscans give nearly identical results as shown in the article. In the SBML version model the volumes of the mitochondrion, the cytoplasm and the cell were all set to one to obtain the same equations as described in the supplemental materials of the article. The total folate is equally split between the cytosol and the mitochondrion and divided by 3/4 for the cytosol and 1/4 for the mitochondrion, respectively. To obtain an SBML model in which the volumes of the compartments, cytosol and mito , are used, the model needs to be altered as follows: for the initial distribution of folate the terms 3/4 and 1/4 have to be replaced by volumes of cytosol and mitochondria respectively in the transport reactions between mitochondrion and cytosol the stoichiometry of the mitochondrial reactants has to be set from 3 to 1 and in the first part of the according rate laws the factor mito/3 should simply be replaced with mito . the stoichiometries of src and dmg have to be changed to cell/mito for mitchondrial and cell/cytosol for cytosolic reactions involving these two species. While the concentrations stay the same after these alteration, the reaction fluxes change by a factor of cytosol and mito for cytosolic and mitchondrial reactions, respectively. Originally created by libAntimony v1.3 (using libSBML 3.4.1) This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:Purpose: We examined the impact of niacin on muscle gene expression in mitochondrial myopathy patients and healthy controls. Methods: Muscle transcriptomics profiles were generated using global transcriptomics analysis by RNA sequencing which was performed by the Beijing Genomic Institute (BGI) using their standard protocols Results: The pathway enrichment analysis of RNA-sequencing data indicated that phagosome formation, serine/glycine/one-carbon pathways (de novo serine biosynthesis, purine degradation, glutathione metabolism), LXR/RXR activation, eicosanoid, glycoprotein 6, atherosclerosis, iron homeostasis and cAMP-mediated signalling pathways were among the most significantly changed in patients. Only five and two of the disease associated pathways remained significantly changed after 4- and 10-month supplementation, respectively, in patients as compared to controls. The most prominent niacin-related transcriptomic change in patients’ muscle (patient 10-months on niacin vs patient baseline) was wide-spread downregulation of mTOR-dependent cytoplasmic translation, involving a large number of cytoplasmic ribosome subunits as well as translation initiation factor eIF1. In patients, niacin activated also the peroxisome proliferator-activated receptor signaling pathway, known to induce mitochondrial biogenesis. Niacin also led to decreased atherosclerosis signaling including lowered apolipoprotein expression in patients. The healthy control muscles showed only few changes after 4-months of niacin. To examine in detail the effects of NAD-booster niacin in the mitochondrial integrated stress response (ISRmt), we studied the effects NAD+ boosting for the expression of 24 ISRmt target genes in the patients’ muscle. The analysis confirmed wide-spread induction of these genes, but their expression was unaffected by niacin (ATF5 and its targets ASNS, TRIB3, FGF21, GDF15, MTHFD2, and MTHFD1L; de novo synthesis of serine, PSAT1, PHGDH and SHMT2; glutathione metabolism GPX3 and GSR; and unfolded protein response ER CHOP). Conclusions: These results showed that niacin modulated the expression of disease associated pathways and suppressed mTOR signalling in patients but niacin did not affect disease-related ISRmt signalling.

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Amino acid deprivation due to overexpression of UCP1 in skeletal muscle: signalling via FGF-21

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