Abstract 20140: Minibrain Relate Kinase / Dyrk1B Links Skeletal Muscle Glycolytic Metabolism with Insulin Resistance and Causes Metabolic Syndrome

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Mohsen Fathzadeh ◽  
Ali Reza Keramati ◽  
Gwang Go ◽  
Rajvir Singh ◽  
Kazem Sarajzadeh ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Protein Expression ◽  
Ppar Gamma ◽  
Glycolytic Metabolism ◽  
Expression Levels ◽  
Fiber Composition ◽  
Mutation Carriers ◽  
Fast Twitch

We have identified a novel nonconservative mutation in Minibrain related serine/threonine kinase (Mirk/ Dyrk1B) in outlier kindreds with metabolic syndrome. The mutation substitutes cysteine for arginine (R102C) and segregates with most traits of metabolic syndrome, including central obesity, diabetes and hypertension. Oral glucose tolerance test (OGTT) in young nondiabetic mutation carriers revealed insulin resistance compared to noncarrier family members. Since skeletal muscle (SM) is the largest organ for glucose uptake and metabolism, we obtained Vastus Lateralis biopsies of mutation carriers and their unaffected relatives and examined them for gene/protein expression by deep RNA sequencing (RNA-Seq) and Western blot analysis and for fiber composition by immunostaining. The fiber composition data demonstrated fewer slow-twitch fibers (35% vs. 75%) and more fast -twitch fibers (65% vs. 25%) in SM of mutation carriers vs. controls. Interestingly, there were increased protein expression levels of fast-twitch fiber type proteins (MYH11, MYLPF), pyruvate dehydrogenase kinase, pyruvate kinase, and neuronal nitric oxide synthase in SM of mutation carriers vs. noncarriers. Consistent with these findings, the protein expression levels of the master regulator of cellular energy metabolism mitochondrial biogenesis, PPAR-gamma coactivator (PGC-1a), were reduced and the nuclear expression levels of FOXO1 and NFAT were increased. Similar findings were observed when wildtype and mutant (R102C) Dyrk1B were overexpressed in C2C12 cells. The overexpression of the kinase deficient Dyrk1B (Y271/273F) similarly resulted in reduced expression of PGC-1a and increased expression of nuclear FOXO1, suggesting kinase independent effects. Taken together, these findings suggest that enhanced kinase-independent activities of Dyrk1B, either through increased expression or by its gain of function mutation R102C induce insulin resistance by promoting glycolytic metabolism and reducing oxidative phosphorylation. In conclusion, Dyrk1B is a potential target for development of novel drugs that aim to enhance skeletal muscle insulin sensitivity.

Effect of voluntary exercise on peripheral tissue glucocorticoid receptor content and the expression and activity of 11β-HSD1 in the Syrian hamster

2006 ◽  
Vol 100 (5) ◽  
pp. 1483-1488 ◽  
Author(s):  
Agnes E. Coutinho ◽  
Jonathan E. Campbell ◽  
Sergiu Fediuc ◽  
Michael C. Riddell
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Enzyme Activity ◽  
Adipose Tissue ◽  
Protein Expression ◽  
Aerobic Exercise ◽  
Visceral Adipose Tissue ◽  
The Metabolic Syndrome ◽  
Visceral Adipose

Recent findings indicate that elevated levels of glucocorticoids (GC), governed by the expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and GC receptors (GR), in visceral adipose tissue and skeletal muscle lead to increased insulin resistance and the metabolic syndrome. Paradoxically, evidence indicates that aerobic exercise attenuates the development of the metabolic syndrome even though it stimulates acute increases in circulating GC levels. To investigate the hypothesis that training alters peripheral GC action to maintain insulin sensitivity, young male hamsters were randomly divided into sedentary (S) and trained (T) groups ( n = 8 in each). The T group had 24-h access to running wheels over 4 wk of study. In muscle, T hamsters had lower 11β-HSD1 protein expression (19.2 ± 1.40 vs. 22.2 ± 0.96 optical density, P < 0.05), similar 11β-HSD1 enzyme activity (0.9 ± 0.27% vs. 1.1 ± 0.26), and lower GR protein expression (9.7 ± 1.86 vs. 15.1 ± 1.78 optical density, P < 0.01) than S hamsters. In liver, 11β-HSD1 protein expression tended to be lower in T compared with S (19.2 ± 0.56 vs. 21.4 ± 1.05, P = 0.07), whereas both enzyme activity and GR protein expression were similar. In contrast, visceral adipose tissue contained ∼2.7-fold higher 11β-HSD1 enzyme activity in T compared with S (12.9 ± 3.3 vs. 4.8 ± 1.5% conversion, P < 0.05) but was considerably smaller in mass (0.24 ± 0.02 vs. 0.71 ± 0.06 g). Thus the intracellular adaptation of GC regulators to exercise is tissue specific, resulting in decreases in GC action in skeletal muscle and increases in GC action in visceral fat. These adaptations may have important implications in explaining the protective effects of aerobic exercise on insulin resistance and other symptoms of the metabolic syndrome.

scholarly journals Upregulation of skeletal muscle inflammatory genes links inflammation with insulin resistance in women with the metabolic syndrome

2013 ◽  
Vol 98 (10) ◽  
pp. 1485-1494 ◽  
Author(s):  
Fleur Poelkens ◽  
Gerwen Lammers ◽  
Elisabeth M. Pardoel ◽  
Cees J. Tack ◽  
Maria T. E. Hopman
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Inflammatory Genes ◽  
The Metabolic Syndrome

scholarly journals Fibre-type specific modification of the activity and regulation of skeletal muscle pyruvate dehydrogenase kinase (PDK) by prolonged starvation and refeeding is associated with targeted regulation of PDK isoenzyme 4 expression

2000 ◽  
Vol 346 (3) ◽  
pp. 651-657 ◽  
Author(s):  
Mary C. SUGDEN ◽  
Alexandra KRAUS ◽  
Robert A. HARRIS ◽  
Mark J. HOLNESS
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Pyruvate Dehydrogenase ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Pyruvate Dehydrogenase Kinase ◽  
Acid Cycle ◽  
Slow Twitch ◽  
Fast Twitch ◽  
Anterior Tibialis

Using immunoblot analysis with antibodies raised against recombinant pyruvate dehydrogenase kinase (PDK) isoenzymes PDK2 and PDK4, we demonstrate selective changes in PDK isoenzyme expression in slow-twitch versus fast-twitch skeletal muscle types in response to prolonged (48 h) starvation and refeeding after starvation. Starvation increased PDK activity in both slow-twitch (soleus) and fast-twitch (anterior tibialis) skeletal muscle and was associated with loss of sensitivity of PDK to inhibition by pyruvate, with a greater effect in anterior tibialis. Starvation significantly increased PDK4 protein expression in both soleus and anterior tibialis, with a greater response in anterior tibialis. Starvation did not effect PDK2 protein expression in soleus, but modestly increased PDK2 expression in anterior tibialis. Refeeding for 4 h partially reversed the effect of 48-h starvation on PDK activity and PDK4 expression in both soleus and anterior tibialis, but the response was more marked in soleus than in anterior tibialis. Pyruvate sensitivity of PDK activity was also partially restored by refeeding, again with the greater response in soleus. It is concluded that targeted regulation of PDK4 isoenzyme expression in skeletal muscle in response to starvation and refeeding underlies the modulation of the regulatory characteristics of PDK in vivo. We propose that switching from a pyruvate-sensitive to a pyruvate-insensitive PDK isoenzyme in starvation (a) maintains a sufficiently high pyruvate concentration to ensure that the glucose → alanine → glucose cycle is not impaired, and (b) may ‘spare’ pyruvate for anaplerotic entry into the tricarboxylic acid cycle to support the entry of acetyl-CoA derived from fatty acid (FA) oxidation into the tricarboxylic acid cycle. We further speculate that FA oxidation by skeletal muscle is both forced and facilitated by upregulation of PDK4, which is perceived as an essential component of the operation of the glucose-FA cycle in starvation.

scholarly journals Meta-Transcriptomic Analysis of RNAseq Data Reveals Pacu and Loach Fish with Unusually High Levels of Myoglobin Expression in Skeletal Muscles

Animals ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1130
Author(s):  
Rui-Yi Chen ◽  
Bui Thi Ngoc Hieu ◽  
Gilbert Audira ◽  
Bao Lou ◽  
Ming-Der Lin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Fish Species ◽  
Binding Proteins ◽  
Binding Protein ◽  
Transcriptomic Analysis ◽  
Oxygen Binding ◽  
Putative Gene ◽  
Expression Levels ◽  
Rnaseq Data

Oxygen-binding proteins, such as myoglobin, hemoglobin, neuroglobin, and cytoglobin, play a role in oxygen binding and delivery to tissues. In icefish, the loss of myoglobin and hemoglobin genes has been reported to be an adaptive evolution event. This interesting finding prompted us to exam oxygen-binding protein expression in diverse fish species. Taking advantage of substantial RNAseq data deposited in the NCBI (National Center for Biotechnology Information) database, we adopted a meta-transcriptomic approach to explore and compare four oxygen-binding protein gene expression levels in the skeletal muscle of 25 diverse fish species for the first time. RNAseq data were downloaded from the NCBI Sequence Read Archive (SRA) database, and de novo assembly was performed to generate transcript contigs. The genes encoding oxygen-binding proteins were then identified by the BLAST search, and the relative expression level of oxygen-binding protein genes was normalized by the RPKM (Reads per Kilobase Million) method. By performing expression profiling, hierarchy clustering, and principal component analysis, pacu and loach fish were noticed by their high myoglobin expression levels in skeletal muscle tissues among 25 diverse fish species. In conclusion, we demonstrated that meta-transcriptomic analysis of RNAseq data is an informative approach to compare the oxygen-binding protein expression and putative gene expansion event in fish.

scholarly journals The Adipokines in Cancer Cachexia

2020 ◽  
Vol 21 (14) ◽  
pp. 4860 ◽  
Author(s):  
Michele Mannelli ◽  
Tania Gamberi ◽  
Francesca Magherini ◽  
Tania Fiaschi
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Therapeutic Strategies ◽  
Skeletal Muscle Wasting ◽  
Circulating Levels

Cachexia is a devastating pathology induced by several kinds of diseases, including cancer. The hallmark of cancer cachexia is an extended weight loss mainly due to skeletal muscle wasting and fat storage depletion from adipose tissue. The latter exerts key functions for the health of the whole organism, also through the secretion of several adipokines. These hormones induce a plethora of effects in target tissues, ranging from metabolic to differentiating ones. Conversely, the decrease of the circulating level of several adipokines positively correlates with insulin resistance, metabolic syndrome, diabetes, and cardiovascular disease. A lot of findings suggest that cancer cachexia is associated with changed secretion of adipokines by adipose tissue. In agreement, cachectic patients show often altered circulating levels of adipokines. This review reported the findings of adipokines (leptin, adiponectin, resistin, apelin, and visfatin) in cancer cachexia, highlighting that to study in-depth the involvement of these hormones in this pathology could lead to the development of new therapeutic strategies.

scholarly journals Immobilization rapidly induces thioredoxin-interacting protein gene expression together with insulin resistance in rat skeletal muscle

2018 ◽  
Vol 125 (2) ◽  
pp. 596-604 ◽  
Author(s):  
Emi Kawamoto ◽  
Keigo Tamakoshi ◽  
Song-Gyu Ra ◽  
Hiroyuki Masuda ◽  
Kentaro Kawanaka
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Expression ◽  
Glucose Uptake ◽  
Rapid Development ◽  
Plaster Cast ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Transcription Inhibitor ◽  
Male Wistar Rats

Acute short duration of disuse induces the development of insulin resistance for glucose uptake in rodent skeletal muscle. Because thioredoxin-interacting protein (TXNIP) has been implicated in the downregulation of insulin signaling and glucose uptake, we examined the possibility that muscle disuse rapidly induces insulin resistance via increased TXNIP mRNA and protein expression. Male Wistar rats were subjected to unilateral 6-h hindlimb immobilization by plaster cast. At the end of this period, the soleus muscles from both immobilized and contralateral nonimmobilized hindlimbs were excised and examined. The 6-h immobilization resulted in an increase in TXNIP mRNA and protein expressions together with a decrease in insulin-stimulated 2-deoxyglucose uptake in the rat soleus muscle. Additionally, in the rats euthanized 6 h after the plaster cast removal, TXNIP protein expression and insulin-stimulated glucose uptake in the immobilized muscle had both been restored to a normal level. Various interventions (pretreatment with transcription inhibitor actinomycin D or AMP-dependent protein kinase activator 5-aminoimidazole-4-carboxamide ribonucleotide) also suppressed the increase in TXNIP protein expression in 6-h-immobilized muscle together with partial prevention of insulin resistance for glucose uptake. These results suggested the possibility that increased TXNIP protein expression in immobilized rat soleus muscles was associated with the rapid induction of insulin resistance for glucose uptake in that tissue. NEW & NOTEWORTHY The cellular mechanism by which disuse rapidly induces muscle insulin resistance for glucose uptake remains to be identified. Using a rat hindlimb immobilization model, our findings suggest the possibility that transcriptional upregulation of thioredoxin-interacting protein is associated with the immobilization-induced rapid development of insulin resistance in skeletal muscle.

Shift from slow- to fast-twitch muscle fibres in skeletal muscle of newborn heterozygous and homozygous myostatin-knockout piglets

2019 ◽  
Vol 31 (10) ◽  
pp. 1628 ◽  
Author(s):  
Mei-Fu Xuan ◽  
Zhao-Bo Luo ◽  
Jun-Xia Wang ◽  
Qing Guo ◽  
Sheng-Zhong Han ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Muscle Development ◽  
Transforming Growth Factor ◽  
Myogenic Differentiation ◽  
Muscle Fibres ◽  
Skeletal Muscle Development ◽  
Cross Sectional ◽  
Gene And Protein Expression ◽  
Fast Twitch

Myostatin (MSTN) is a member of the transforming growth factor-β superfamily that negatively regulates skeletal muscle development. A lack of MSTN induces muscle hypertrophy and increases formation of fast-twitch (Type II) muscle fibres. This study investigated muscle development in newborn heterozygous (MSTN+/−) and homozygous (MSTN−/−) MSTN-knockout piglets. Detailed morphological and gene and protein expression analyses were performed of the biceps femoris, semitendinosus and diaphragm of MSTN+/−, MSTN−/− and wild-type (WT) piglets. Haematoxylin–eosin staining revealed that the cross-sectional area of muscle fibres was significantly larger in MSTN-knockout than WT piglets. ATPase staining demonstrated that the percentage of Type IIb and IIa muscle fibres was significantly higher in MSTN−/− and MSTN+/− piglets respectively than in WT piglets. Western blotting showed that protein expression of myosin heavy chain-I was reduced in muscles of MSTN-knockout piglets. Quantitative reverse transcription–polymerase chain reaction revealed that, compared with WT piglets, myogenic differentiation factor (MyoD) mRNA expression in muscles was 1.3- to 2-fold higher in MSTN+/− piglets and 1.8- to 3.5-fold higher MSTN−/− piglets (P&lt;0.05 and P&lt;0.01 respectively). However, expression of myocyte enhancer factor 2C (MEF2C) mRNA in muscles was significantly lower in MSTN+/− than WT piglets (P&lt;0.05). MSTN plays an important role in skeletal muscle development and regulates muscle fibre type by modulating the gene expression of MyoD and MEF2C in newborn piglets.

scholarly journals Dicarbonyl stress and glyoxalase enzyme system regulation in human skeletal muscle

2018 ◽  
Vol 314 (2) ◽  
pp. R181-R190 ◽  
Author(s):  
Jacob T. Mey ◽  
Brian K. Blackburn ◽  
Edwin R. Miranda ◽  
Alec B. Chaves ◽  
Joan Briller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Expression ◽  
Enzyme System ◽  
Vastus Lateralis ◽  
Negative Regulator ◽  
Glucose Disposal ◽  
Carbonyl Stress ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance

Skeletal muscle insulin resistance is a hallmark of Type 2 diabetes (T2DM) and may be exacerbated by protein modifications by methylglyoxal (MG), known as dicarbonyl stress. The glyoxalase enzyme system composed of glyoxalase 1/2 (GLO1/GLO2) is the natural defense against dicarbonyl stress, yet its protein expression, activity, and regulation remain largely unexplored in skeletal muscle. Therefore, this study investigated dicarbonyl stress and the glyoxalase enzyme system in the skeletal muscle of subjects with T2DM (age: 56 ± 5 yr.; BMI: 32 ± 2 kg/m2) compared with lean healthy control subjects (LHC; age: 27 ± 1 yr.; BMI: 22 ± 1 kg/m2). Skeletal muscle biopsies obtained from the vastus lateralis at basal and insulin-stimulated states of the hyperinsulinemic (40 mU·m−2·min−1)–euglycemic (5 mM) clamp were analyzed for proteins related to dicarbonyl stress and glyoxalase biology. At baseline, T2DM had increased carbonyl stress and lower GLO1 protein expression (−78.8%), which inversely correlated with BMI, percent body fat, and HOMA-IR, while positively correlating with clamp-derived glucose disposal rates. T2DM also had lower NRF2 protein expression (−31.6%), which is a positive regulator of GLO1, while Keap1 protein expression, a negative regulator of GLO1, was elevated (207%). Additionally, insulin stimulation during the clamp had a differential effect on NRF2, Keap1, and MG-modified protein expression. These data suggest that dicarbonyl stress and the glyoxalase enzyme system are dysregulated in T2DM skeletal muscle and may underlie skeletal muscle insulin resistance. Whether these phenotypic differences contribute to the development of T2DM warrants further investigation.

scholarly journals Altered Skeletal Muscle Fiber Composition and Size Precede Whole-Body Insulin Resistance in Young Men with Low Birth Weight

2007 ◽  
Vol 92 (4) ◽  
pp. 1530-1534 ◽  
Author(s):  
Christine B. Jensen ◽  
Heidi Storgaard ◽  
Sten Madsbad ◽  
Erik A. Richter ◽  
Allan A. Vaag
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Birth Weight ◽  
Capillary Density ◽  
Whole Body ◽  
Type I ◽  
Normal Birth ◽  
Fiber Composition ◽  
Type I Fibers

Abstract Context: Low birth weight (LBW), a surrogate marker of an adverse fetal milieu, is linked to muscle insulin resistance, impaired insulin-stimulated glycolysis, and future risk of type 2 diabetes. Skeletal muscle mass, fiber composition, and capillary density are important determinants of muscle function and metabolism, and alterations have been implicated in the pathogenesis of insulin resistance. Objective: The aim of this study was to investigate whether an adverse fetal environment (LBW) induces permanent changes in skeletal muscle morphology, which may contribute to the dysmetabolic phenotype associated with LBW. Design and Subjects: Vastus lateralis muscle was obtained by percutaneous biopsy from 20 healthy 19-yr-old men with birth weights at 10th percentile or lower for gestational age (LBW) and 20 normal birth weight controls, matched for body fat, physical fitness, and whole-body glucose disposal. Myofibrillar ATPase staining was used to classify muscle fibers as type I, IIa, and IIx (formerly type IIb), and double immunostaining was performed to stain capillaries (LBW, n = 8; normal birth weight, n = 12). Results: LBW was associated with increased proportion of type IIx fibers (+66%; P = 0.03), at the expense of decreased type IIa fibers (−22%; P = 0.003). No significant change was observed in proportion of type I fibers (+16%; P = 0.11). In addition, mean area of type IIa fibers was increased (+29%; P = 0.01) and tended to be increased for type I fibers as well (+17%; P = 0.08). Capillary density was not significantly different between groups. Conclusion: Alterations in fiber composition and size may contribute to development of type 2 diabetes in individuals with LBW.

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