| 1. |
- Al-Khalili, L, et al.
(författare)
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Prior serum- and AICAR-induced AMPK activation in primary human myocytes does not lead to subsequent increase in insulin-stimulated glucose uptake
- 2004
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 287:3, s. E553-E557
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Tidskriftsartikel (refereegranskat)abstract
- Exposing isolated rat skeletal muscle to 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside [AICAR, a pharmacological activator of AMP-activated protein kinase (AMPK)] plus serum leads to a subsequent increase in insulin-stimulated glucose transport (Fisher JS, Gao J, Han DH, Holloszy JO, and Nolte LA. Am J Physiol Endocrinol Metab 282: E18–E23, 2002). Our goal was to determine whether preincubation of primary human skeletal muscle cells with human serum and AICAR (Serum+AICAR) would also induce a subsequent elevation in insulin-stimulated glucose uptake. Cells were preincubated for 1 h under 4 conditions: 1) without AICAR or serum (Control), 2) with serum, 3) with AICAR, or 4) with Serum+AICAR. Some cells were then collected for immunoblot analysis to assess phosphorylation of AMPK (pAMPK) and its substrate acetyl-CoA carboxylase (ACC). Other cells were incubated for an additional 4 h without AICAR or serum and then used to measure basal or insulin-stimulated 2-deoxyglucose (2-DG) uptake. Level of pAMPK was increased ( P < 0.01) for myotubes exposed to Serum+AICAR vs. all other groups. Phosphorylated ACC (pACC) levels were higher for both Serum+AICAR ( P < 0.05) and AICAR ( P < 0.05) vs. Control and Serum groups. Basal ( P < 0.05) and 1.2 nM insulin-stimulated ( P < 0.005) 2-DG uptake was higher for Serum vs. all other preincubation conditions at equal insulin concentration. Regardless of insulin concentration (0, 1.2, or 18 nM), 2-DG was unaltered in cells preincubated with Serum+AICAR vs. Control cells. In contrast to results with isolated rat skeletal muscle, increasing the pAMPK and pACC in human myocytes via preincubation with Serum+AICAR was insufficient to lead to a subsequent enhancement in insulin-stimulated glucose uptake.
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| 2. |
- Benziane, B, et al.
(författare)
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Divergent cell signaling after short-term intensified endurance training in human skeletal muscle
- 2008
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 295:6, s. E1427-E1438
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Tidskriftsartikel (refereegranskat)abstract
- Endurance training represents one extreme in the continuum of skeletal muscle plasticity. The molecular signals elicited in response to acute and chronic exercise and the integration of multiple intracellular pathways are incompletely understood. We determined the effect of 10 days of intensified cycle training on signal transduction in nine inactive males in response to a 1-h acute bout of cycling at the same absolute workload (164 ± 9 W). Muscle biopsies were taken at rest and immediately and 3 h after the acute exercise. The metabolic signaling pathways, including AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), demonstrated divergent regulation by exercise after training. AMPK phosphorylation increased in response to exercise (∼16-fold; P < 0.05), which was abrogated posttraining ( P < 0.01). In contrast, mTOR phosphorylation increased in response to exercise (∼2-fold; P < 0.01), which was augmented posttraining ( P < 0.01) in the presence of increased mTOR expression ( P < 0.05). Exercise elicited divergent effects on mitogen-activated protein kinase (MAPK) pathways after training, with exercise-induced extracellular signal-regulated kinase (ERK) 1/2 phosphorylation being abolished ( P < 0.01) and p38 MAPK maintained. Finally, calmodulin kinase II (CaMKII) exercise-induced phosphorylation and activity were maintained ( P < 0.01), despite increased expression (∼2-fold; P < 0.05). In conclusion, 10 days of intensified endurance training attenuated AMPK, ERK1/2, and mTOR, but not CaMKII and p38 MAPK signaling, highlighting molecular pathways important for rapid functional adaptations and maintenance in response to intensified endurance exercise and training.
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| 3. |
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| 4. |
- Deshmukh, AS, et al.
(författare)
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Role of the AMPKgamma3 isoform in hypoxia-stimulated glucose transport in glycolytic skeletal muscle
- 2009
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 297:6, s. E1388-E1394
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Tidskriftsartikel (refereegranskat)abstract
- Skeletal muscle glucose transport is regulated via the canonical insulin-signaling cascade as well as by energy-sensing signals. 5′-AMP-activated protein kinase (AMPK) has been implicated in the energy status regulation of glucose transport. We determined the role of the AMPKγ3 isoform in hypoxia-mediated energy status signaling and glucose transport in fast-twitch glycolytic extensor digitorum longus (EDL) muscle from AMPKγ3-knockout (KO) mice and wild-type mice. Although hypoxia increased glucose transport ( P < 0.001) in wild-type mice, this effect was attenuated in AMPKγ3-KO mice (45% reduction, P < 0.01). The role of Ca2+-mediated signaling was tested using the Ca2+/calmodulin competitive inhibitor KN-93. KN-93 exposure reduced hypoxia-mediated glucose transport in AMPKγ3-KO and wild-type mice ( P < 0.05). To further explore the underlying signaling mechanisms, phosphorylation of CaMKII, AMPK, ACC, and TBC1D1/D4 as well as isoform-specific AMPK activity was determined. Basal and hypoxia-mediated phosphorylation of CaMKII, AMPK, and ACC as well as α1- and α2-associated AMPK activity was comparable between AMPKγ3-KO and wild-type mice. KN-93 reduced hypoxia-mediated CaMKII phosphorylation in AMPKγ3-KO and wild-type mice ( P < 0.05), whereas phosphorylation of AMPK and ACC as well as α1- and α2-associated AMPK activity was unaltered. Hypoxia increased TBC1D1/D4 phosphorylation in AMPKγ3-KO and wild-type mice ( P < 0.001). KN-93 exposure prevented this effect in AMPKγ3-KO, but not in wild-type mice. Taken together, we provide direct evidence for a role of the AMPKγ3 isoform in hypoxia-mediated glucose transport in glycolytic muscle. Moreover, hypoxia-mediated TBC1D1/D4 phosphorylation was uncoupled from glucose transport in AMPKγ3-KO mice, indicating that TBC1D1/D4-independent mechanisms contribute to glucose transport in skeletal muscle.
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| 5. |
- Egan, B, et al.
(författare)
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Hunting for the SNARK in metabolic disease
- 2009
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 296:5, s. E969-E972
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 6. |
- Holmstrom, MH, et al.
(författare)
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Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes
- 2012
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 302:6, s. E731-E739
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Tidskriftsartikel (refereegranskat)abstract
- The tissue-specific role of mitochondrial respiratory capacity in the development of insulin resistance and type 2 diabetes is unclear. We determined mitochondrial function in glycolytic and oxidative skeletal muscle and liver from lean (+/ ?) and obese diabetic ( db/db) mice. In lean mice, the mitochondrial respiration pattern differed between tissues. Tissue-specific mitochondrial profiles were then compared between lean and db/db mice. In liver, mitochondrial respiratory capacity and protein expression, including peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), was decreased in db/db mice, consistent with increased mitochondrial fission. In glycolytic muscle, mitochondrial respiration, as well as protein and mRNA expression of mitochondrial markers, was increased in db/db mice, suggesting increased mitochondrial content and fatty acid oxidation capacity. In oxidative muscle, mitochondrial complex I function and PGC-1α and mitochondrial transcription factor A (TFAM) protein levels were decreased in db/db mice, along with increased level of proteins related to mitochondrial dynamics. In conclusion, mitochondrial respiratory performance is under the control of tissue-specific mechanisms and is not uniformly altered in response to obesity. Furthermore, insulin resistance in glycolytic skeletal muscle can be maintained by a mechanism independent of mitochondrial dysfunction. Conversely, insulin resistance in liver and oxidative skeletal muscle from db/db mice is coincident with mitochondrial dysfunction.
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| 7. |
- Jiang, LQ, et al.
(författare)
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Autocrine role of interleukin-13 on skeletal muscle glucose metabolism in type 2 diabetic patients involves microRNA let-7
- 2013
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 305:11, s. E1359-E1366
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Tidskriftsartikel (refereegranskat)abstract
- Low-grade inflammation associated with type 2 diabetes (T2DM) is postulated to exacerbate insulin resistance. We report that serum levels, as well as IL-13 secreted from cultured skeletal muscle, are reduced in T2DM vs. normal glucose-tolerant (NGT) subjects. IL-13 exposure increases skeletal muscle glucose uptake, oxidation, and glycogen synthesis via an Akt-dependent mechanism. Expression of microRNA let-7a and let-7d, which are direct translational repressors of the IL-13 gene, was increased in skeletal muscle from T2DM patients. Overexpression of let-7a and let-7d in cultured myotubes reduced IL-13 secretion. Furthermore, basal glycogen synthesis was reduced in cultured myotubes exposed to an IL-13-neutralizing antibody. Thus, IL-13 is synthesized and released by skeletal muscle through a mechanism involving let-7, and this effect is attenuated in skeletal muscle from insulin-resistant T2DM patients. In conclusion, IL-13 plays an autocrine role in skeletal muscle to increase glucose uptake and metabolism, suggesting a role in glucose homeostasis in metabolic disease.
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| 8. |
- Jiang, LQ, et al.
(författare)
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Constitutively active calcineurin in skeletal muscle increases endurance performance and mitochondrial respiratory capacity
- 2010
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 298:1, s. E8-E16
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Tidskriftsartikel (refereegranskat)abstract
- Expression of an activated form of calcineurin in skeletal muscle selectively up-regulates slow-fiber-specific gene expression. Here, we tested the hypothesis that expression of activated calcineurin in skeletal muscle influences body composition, energy homeostasis, and exercise performance. Using transgenic mice expressing activated calcineurin (CnA*) in skeletal muscle (MCK-CnA* transgenic mice), we determined whether skeletal muscle reprogramming by calcineurin activation affects exercise performance and skeletal muscle mitochondrial function. Body weight and extensor digitorum longus (EDL) skeletal muscle weight were reduced 10% in MCK-CnA* mice compared with wild-type littermates. Basal oxygen consumption, food intake, and voluntary exercise behavior were unchanged between MCK-CnA* and wild-type mice. However, when total energy expenditure was normalized by fat-free mass, energy expenditure was increased in MCK-CnA* mice. An endurance performance treadmill running test revealed MCK-CnA* mice are fatigue resistant and run 50% farther before exhaustion. After a standardized exercise bout, glycogen and triglyceride content in EDL muscle was higher in MCK-CnA* vs. wild-type mice. Mitochondrial respiratory capacity was increased 35% in EDL muscle from resting MCK-CnA* mice. In conclusion, our results provide evidence to support the hypothesis that calcineurin activation in skeletal muscle increases mitochondrial oxidative function and energy substrate storage, which contributes to enhanced endurance exercise performance. These adaptive changes occur as a consequence of a lifelong expression of a constitutively active calcineurin and mimic the response to chronic endurance training.
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| 9. |
- Jiang, LQ, et al.
(författare)
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Diacylglycerol kinase-δ regulates AMPK signaling, lipid metabolism, and skeletal muscle energetics
- 2016
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 310:1, s. E51-E60
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Tidskriftsartikel (refereegranskat)abstract
- Decrease of AMPK-related signal transduction and insufficient lipid oxidation contributes to the pathogenesis of obesity and type 2 diabetes. Previously, we identified that diacylglycerol kinase-δ (DGKδ), an enzyme involved in triglyceride biosynthesis, is reduced in skeletal muscle from type 2 diabetic patients. Here, we tested the hypothesis that DGKδ plays a role in maintaining appropriate AMPK action in skeletal muscle and energetic aspects of contraction. Voluntary running activity was reduced in DGKδ+/−mice, but glycogen content and mitochondrial markers were unaltered, suggesting that DGKδ deficiency affects skeletal muscle energetics but not mitochondrial protein abundance. We next determined the role of DGKδ in AMPK-related signal transduction and lipid metabolism in isolated skeletal muscle. AMPK activation and signaling were reduced in DGKδ+/−mice, concomitant with impaired lipid oxidation and elevated incorporation of free fatty acids into triglycerides. Strikingly, DGKδ deficiency impaired work performance, as evident by altered force production and relaxation dynamics in response to repeated contractions. In conclusion, DGKδ deficiency impairs AMPK signaling and lipid metabolism, thereby highlighting the deleterious role of excessive lipid metabolites in the development of peripheral insulin resistance and type 2 diabetes pathogenesis. DGKδ deficiency also influences skeletal muscle energetics, which may lead to low physical activity levels in type 2 diabetes.
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| 10. |
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