Phospholipid methylation regulates muscle metabolic rate through Ca2+ transport efficiency

Verkerke, Anthony R.P.; Ferrara, Patrick J.; Lin, Chien-Te; Johnson, Jordan M.; Ryan, Terence E.; Maschek, J. Alan; Eshima, Hiroaki; Paran, Christopher; Laing, Brenton T.; Siripoksup, Piyarat; Tippetts, Trevor S.; Wentzler, Edward J.; Hu, Huang; Spangenburg, Espen E.; Brault, Jeffrey J.; Villanueva, Claudio J.; Summers, Scott A.; Holland, William L.; Cox, James E.; Vance, Dennis E.; Neufer, P. Darrell; Funai, Katsuhiko

doi:10.1038/s42255-019-0111-2

Cited by 36 publications

(48 citation statements)

References 46 publications

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“…In skeletal muscle, phospholipid methyltransferase activity is highly localized in sarcoplasmic reticulum and present to a lesser extent in sarcolemma. Methylation of phosphatidylethanolamine modulates sarcoplasmic reticulum phospholipid composition, which in turn alters the energetic efficiency of SERCA (Ca 2+ uptake / ATP hydrolysis) ion pump, decreasing the skeletal muscle metabolic rate [ 43 – 45 ]. Our results can be explained by a possible inhibition of Ca 2+ uptake under an excess of methylation in the sarcoplasmic reticulum of RPM.…”

Section: Discussionmentioning

confidence: 99%

Preconditioning beef cattle for long-duration transportation stress with rumen-protected methionine supplementation: A nutrigenetics study

et al. 2020

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In general, beef cattle long-distance transportation from cow-calf operations to feedlots or from feedlots to abattoirs is a common situation in the beef industry. The aim of this study was to determine the effect of rumen-protected methionine (RPM) supplementation on a proposed gene network for muscle fatigue, creatine synthesis (CKM), and reactive oxygen species (ROS) metabolism after a transportation simulation in a test track. Angus × Simmental heifers (n = 18) were stratified by body weight (408 ± 64 kg; BW) and randomly assigned to dietary treatments: 1) control diet (CTRL) or 2) control diet + 8 gr/hd/day of topdressed rumen-protected methionine (RPM). After an adaptation period to Calan gates, animals received the mentioned dietary treatment consisting of Bermuda hay ad libitum and a soy hulls and corn gluten feed based supplement. After 45 days of supplementation, animals were loaded onto a trailer and transported for 22 hours (long-term transportation). Longissimus muscle biopsies, BW and blood samples were obtained on day 0 (Baseline), 43 (Pre-transport; PRET), and 46 (Post-transport; POST). Heifers' average daily gain did not differ between baseline and PRET. Control heifer's shrink was 10% of BW while RPM heifers shrink was 8%. Serum cortisol decreased, and glucose and creatine kinase levels increased after transportation, but no differences were observed between treatments. Messenger RNA was extracted from skeletal muscle tissue and gene expression analysis was performed by RT-qPCR. Results showed that AHCY and DNMT3A (DNA methylation), SSPN (Sarcoglycan complex), and SOD2 (Oxidative Stress-ROS) were upregulated in CTRL between baseline and PRET and, decreased between pre and POST while they remained constant for RPM. Furthermore, CKM was not affected by treatments. In conclusion, RPM supplementation may affect ROS production and enhance DNA hypermethylation, after a long-term transportation.

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Section: Discussionmentioning

confidence: 99%

Preconditioning beef cattle for long-duration transportation stress with rumen-protected methionine supplementation: A nutrigenetics study

et al. 2020

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“…The PEMTKO mice were a generous gift from Dr. Dennis Vance at the University of Alberta [20]. We generated PEMT conditional knockout mice (PEMTcKO, with exon 3 of the Pemt gene flanked with loxP sites) [21] that were crossed to UCP1-Cre mice (Jackson Laboratory, stock #: 024670), albumin-Cre mice (Jackson Laboratory, stock #: 003574), HSA-MerCreMer mice (a gift from Dr. Karyn Esser, University of Florida), or adiponectin-Cre mice (Jackson Laboratory, stock #: 028020) to obtain tissue-specific knockout mice. The tafazzin knockdown (TAZKD) mice were obtained from Jackson Laboratory (stock #: 014648).…”

Section: Methodsmentioning

confidence: 99%

Alternative splicing of UCP1 by non-cell-autonomous action of PEMT

Johnson

Verkerke

Maschek

et al. 2020

Molecular Metabolism

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ObjectivePhosphatidylethanolamine methyltransferase (PEMT) generates phosphatidylcholine (PC), the most abundant phospholipid in the mitochondria and an important acyl chain donor for cardiolipin (CL) biosynthesis. Mice lacking PEMT (PEMTKO) are cold-intolerant when fed a high-fat diet (HFD) due to unclear mechanisms. The purpose of this study was to determine whether PEMT-derived phospholipids are important for the function of uncoupling protein 1 (UCP1) and thus for maintenance of core temperature.MethodsTo test whether PEMT-derived phospholipids are important for UCP1 function, we examined cold-tolerance and brown adipose (BAT) mitochondria from PEMTKO mice with or without HFD feeding. We complemented these studies with experiments on mice lacking functional CL due to tafazzin knockdown (TAZKD). We generated several conditional mouse models to study the tissue-specific roles of PEMT, including mice with BAT-specific knockout of PEMT (PEMT-BKO).ResultsChow- and HFD-fed PEMTKO mice completely lacked UCP1 protein in BAT, despite a lack of difference in mRNA levels, and the mice were accordingly cold-intolerant. While HFD-fed PEMTKO mice exhibited reduced mitochondrial CL content, this was not observed in chow-fed PEMTKO mice or TAZKD mice, indicating that the lack of UCP1 was not attributable to CL deficiency. Surprisingly, the PEMT-BKO mice exhibited normal UCP1 protein levels. Knockout of PEMT in the adipose tissue (PEMT-AKO), liver (PEMT-LKO), or skeletal muscle (PEMT-MKO) also did not affect UCP1 protein levels, suggesting that lack of PEMT in other non-UCP1-expressing cells communicates to BAT to suppress UCP1. Instead, we identified an untranslated UCP1 splice variant that was triggered during the perinatal period in the PEMTKO mice.ConclusionsPEMT is required for UCP1 splicing that yields functional protein. This effect is derived by PEMT in nonadipocytes that communicates to BAT during embryonic development. Future research will focus on identifying the non-cell-autonomous PEMT-dependent mechanism of UCP1 splicing.

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“…[40][41][42] However, reducing SERCA's coupling ratio creates a futile Ca 2+ cycle, where more ATP is required to transport Ca 2+ into the SR. Studies aimed at lowering SERCA's coupling ratio have all shown therapeutic promise in the fight against diet-induced obesity and glucose intolerance. [43][44][45][46] NNAT shares 50% sequence homology with the allosteric SERCA regulator, PLN (Figure 2A). 27 PLN acts by binding to the SERCA transmembrane domain causing conformational changes that decrease SERCA's affinity for Ca 2+ .…”

Section: Serca Uncoupling: a Role For Nnat?mentioning

confidence: 99%

Neuronatin regulates whole‐body metabolism: is thermogenesis involved?

Braun¹,

Geromella²,

Hamstra³

et al. 2020

FASEB BioAdvances

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The neuronatin (NNAT, 3.9 kb) gene is paternally inherited with the maternal allele silenced via DNA methylation. 1,2 Genomic imprinting such as this results in monoallelic expression-a characteristic of several other genes critical for growth, development, and metabolism. 3 Through alternative splicing, NNAT mRNA produces two isoforms, NNATα (81 amino acids) and NNATβ (54 amino acids), 4,5 though the extent with which these isoforms are functionally redundant or divergent remain to be uncovered. NNAT/Nnat mRNA is enriched in the developing brain, and while downregulated

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Phospholipid methylation regulates muscle metabolic rate through Ca2+ transport efficiency

Cited by 36 publications

References 46 publications

Preconditioning beef cattle for long-duration transportation stress with rumen-protected methionine supplementation: A nutrigenetics study

Preconditioning beef cattle for long-duration transportation stress with rumen-protected methionine supplementation: A nutrigenetics study

Alternative splicing of UCP1 by non-cell-autonomous action of PEMT

Neuronatin regulates whole‐body metabolism: is thermogenesis involved?

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