scholarly journals MicroRNA-mediated inhibition of AMPK coordinates tissue-specific downregulation of skeletal muscle metabolism in hypoxic naked mole-rats

2021 ◽  
Vol 224 (15) ◽  
Author(s):  
Hanane Hadj-Moussa ◽  
Sarah Chiasson ◽  
Hang Cheng ◽  
Liam Eaton ◽  
Kenneth B. Storey ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Rate ◽  
Glycogen Synthase ◽  
Muscle Metabolism ◽  
Severe Hypoxia ◽  
Post Translational Modification ◽  
Rat Skeletal Muscle ◽  
Tissue Specific ◽  
Mole Rat ◽  
Naked Mole Rat

ABSTRACT Naked mole-rats reduce their metabolic requirements to tolerate severe hypoxia. However, the regulatory mechanisms that underpin this metabolic suppression have yet to be elucidated. 5′-AMP-activated protein kinase (AMPK) is the cellular ‘master’ energy effector and we hypothesized that alterations in the AMPK pathway contribute to metabolic reorganization in hypoxic naked mole-rat skeletal muscle. To test this hypothesis, we exposed naked mole-rats to 4 h of normoxia (21% O2) or severe hypoxia (3% O2), while indirectly measuring whole-animal metabolic rate and fuel preference. We then isolated skeletal muscle and assessed protein expression and post-translational modification of AMPK, and downstream changes in key glucose and fatty acid metabolic proteins mediated by AMPK, including acetyl-CoA carboxylase (ACC1), glycogen synthase (GS) and glucose transporters (GLUTs) 1 and 4. We found that in hypoxic naked mole-rats (1) metabolic rate decreased ∼80% and fuel use switched to carbohydrates, and that (2) levels of activated phosphorylated AMPK and GS, and GLUT4 expression were downregulated in skeletal muscle, while ACC1 was unchanged. To explore the regulatory mechanism underlying this hypometabolic state, we used RT-qPCR to examine 55 AMPK-associated microRNAs (miRNAs), which are short non-coding RNA post-transcriptional silencers. We identified changes in 10 miRNAs (three upregulated and seven downregulated) implicated in AMPK downregulation. Our results suggest that miRNAs and post-translational mechanisms coordinately reduce AMPK activity and downregulate metabolism in naked mole-rat skeletal muscle during severe hypoxia. This novel mechanism may support tissue-specific prioritization of energy for more essential organs in hypoxia.

scholarly journals Control of rat skeletal-muscle phosphorylase phosphatase activity by adrenaline

1978 ◽  
Vol 176 (1) ◽  
pp. 347-350 ◽  
Author(s):  
S H Tao ◽  
F L Huang ◽  
A Lynch ◽  
W H Glinsmann
Keyword(s):  
Skeletal Muscle ◽  
Cyclic Amp ◽  
Phosphatase Activity ◽  
Glycogen Synthase ◽  
Rat Skeletal Muscle ◽  
Inhibitor Activity ◽  
Phosphatase Inhibitor ◽  
Heat Stable ◽  
Muscle Phosphorylase ◽  
Isolated Rat

Administration of adrenaline to an isolated rat hindlimb preparation rapidly decreased muscle phosphorylase phosphatase (EC 3.1.3.17) activity and increased heat-stable and trypsin-labile phosphatase inhibitor activity. This was associated with increased tissue cyclic AMP concentrations, phosphorylase (EC 2.4.1.1) activation and glycogen synthase (EC 2.4.1.11) inactivation.

Characterization of GSK-M, a glycogen synthase kinase from rat skeletal muscle

1987 ◽  
Vol 258 (2) ◽  
pp. 470-481 ◽  
Author(s):  
Mohammed G. Hegazy ◽  
Thomas J. Thysseril ◽  
Keith K. Schlender ◽  
Erwin M. Reimann
Keyword(s):  
Skeletal Muscle ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Rat Skeletal Muscle

scholarly journals Piperine’s mitigation of obesity and diabetes can be explained by its up-regulation of the metabolic rate of resting muscle

2016 ◽  
Vol 113 (46) ◽  
pp. 13009-13014 ◽  
Author(s):  
Leonardo Nogara ◽  
Nariman Naber ◽  
Edward Pate ◽  
Marcella Canton ◽  
Carlo Reggiani ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Atpase Activity ◽  
Metabolic Rate ◽  
Muscle Metabolism ◽  
Fluorescent Intensity ◽  
Positive Effects ◽  
Obesity And Diabetes ◽  
Resting Muscle

We identify a target for treating obesity and type 2 diabetes, the consumption of calories by an increase in the metabolic rate of resting skeletal muscle. The metabolic rate of skeletal muscle can be increased by shifting myosin heads from the super-relaxed state (SRX), with a low ATPase activity, to a disordered relaxed state (DRX), with a higher ATPase activity. The shift of myosin heads was detected by a change in fluorescent intensity of a probe attached to the myosin regulatory light chain in skinned skeletal fibers, allowing us to perform a high-throughput screen of 2,128 compounds. The screen identified one compound, which destabilized the super-relaxed state, piperine (the main alkaloid component of black pepper). Destabilization of the SRX by piperine was confirmed by single-nucleotide turnover measurements. The effect was only observed in fast twitch skeletal fibers and not in slow twitch fibers or cardiac tissues. Piperine increased ATPase activity of skinned relaxed fibers by 66 ± 15%. The Kd was ∼2 µM. Piperine had little effect on the mechanics of either fully active or resting muscle fibers. Previous work has shown that piperine can mitigate both obesity and type 2 diabetes in rodent models of these conditions. We propose that the increase in resting muscle metabolism contributes to these positive effects. The results described here show that up-regulation of resting muscle metabolism could treat obesity and type 2 diabetes and that piperine would provide a useful lead compound for the development of these therapies.

scholarly journals Glycogen synthase localization and activity in rat skeletal muscle is strongly dependent on glycogen content

2001 ◽  
Vol 531 (3) ◽  
pp. 757-769 ◽  
Author(s):  
Jakob Nis Nielsen ◽  
Wim Derave ◽  
Søren Kristiansen ◽  
Evelyn Ralston ◽  
Thorkil Ploug ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glycogen Content ◽  
Glycogen Synthase ◽  
Rat Skeletal Muscle

scholarly journals The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin, but not by rapamycin: evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and Raf

1994 ◽  
Vol 303 (1) ◽  
pp. 21-26 ◽  
Author(s):  
D A E Cross ◽  
D R Alessi ◽  
J R Vandenheede ◽  
H E McDowell ◽  
H S Hundal ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Map Kinase ◽  
Protein Phosphatase ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase 3 ◽  
Rat Skeletal Muscle ◽  
S6 Kinase ◽  
P70 S6 Kinase ◽  
Skeletal Muscle Cell Line ◽  
Stimulation Of

Glycogen synthase kinase-3 (GSK3) is inactivated in vitro by p70 S6 kinase or MAP kinase-activated protein kinase-1 beta (MAPKAP kinase-1 beta; also known as Rsk-2). Here we show that GSK3 isoforms are inhibited by 40% within minutes after stimulation of the rat skeletal-muscle cell line L6 with insulin-like growth factor-1 (IGF-1) or insulin. GSK3 was similarly inhibited in rabbit skeletal muscle after an intravenous injection of insulin. Inhibition resulted from increased phosphorylation of GSK3, probably at a serine/threonine residue(s), because it was reversed by incubation with protein phosphatase-2A. Rapamycin blocked the activation of p70 S6 kinase by IGF-1 in L6 cells, but had no effect on the inhibition of GSK3 or the activation of MAPKAP kinase-1 beta. In contrast, wortmannin, a potent inhibitor of PtdIns 3-kinase, prevented the inactivation of GSK3 and the activation of MAPKAP kinase-1 beta and p70 S6 kinase by IGF-1 or insulin. Wortmannin also blocked the activation of p74raf-1. MAP kinase kinase and p42 MAP kinase, but not the formation of GTP-Ras by IGF-1. The results suggest that the stimulation of glycogen synthase by insulin/IGF-1 in skeletal muscle involves the MAP-KAP kinase-1-catalysed inhibition of GSK3, as well as the previously described activation of the glycogen-associated form of protein phosphatase-1.

scholarly journals Increase in Subcellular GSK-3 Clusters in Insulin- and Adrenaline-treated Differentiated Rat Skeletal Muscle Fibres

2020 ◽  
Author(s):  
Katja Fink ◽  
Mateja Lobe Prebil ◽  
Nina Vardjan ◽  
Jorgen Jensen ◽  
Robert Zorec ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Skeletal Muscles ◽  
Metabolic Regulation ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase 3 ◽  
Muscle Fibres ◽  
Optical Section ◽  
Rat Skeletal Muscle ◽  
Average Size ◽  
Skeletal Muscle Fibres

Glycogen synthase kinase 3 (GSK-3) plays an important role in metabolic regulation in skeletal muscles, and both insulin and adrenaline stimulate   GKS-3 phosphorylation. The aim of the present study was to study the effect of insulin and adrenaline on GSK-3 localisation in skeletal muscles.We characterized subcellular localization of (GSK-3) signal protein in fully differentiated muscle fibre by immunofluorescence and confocal microscopy. We stimulated muscle fibres with insulin and/or adrenaline. Images were analysed by segmentation of single central optical section of the muscle.We found GSK-3 to be localised in clusters. The number of GSK-3 clusters and their average size were increased after stimulation with insulin and/or adrenaline. Average GSK-3 particle size is linearly related to their quantity.We conclude that subcellular GSK-3 in isolated skeletal muscle fibres is localized in clusters and clustering increased after stimulation with insulin and/or adrenaline.

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