6‐Gingerol Improves Ectopic Lipid Accumulation, Mitochondrial Dysfunction, and Insulin Resistance in Skeletal Muscle of Ageing Rats: Dual Stimulation of the AMPK/PGC‐1α Signaling Pathway via Plasma Adiponectin and Muscular AdipoR1

To address the potential role of lipotoxicity and mitochondrial function in insulin resistance, we studied mice with high-level expression of uncoupling protein-1 in skeletal muscle (UCP-H mice). Body weight, body length, and bone mineral density were decreased in UCP-H mice compared with wild-type littermates. Forelimb grip strength and muscle mass were strikingly decreased, whereas muscle triglyceride content was increased fivefold in UCP-H mice. Electron microscopy demonstrated lipid accumulation and large mitochondria with abnormal architecture in UCP-H skeletal muscle. ATP content and key mitochondrial proteins were decreased in UCP-H muscle. Despite mitochondrial dysfunction and increased intramyocellular fat, fasting serum glucose was 22% lower and insulin-stimulated glucose transport 80% higher in UCP-H animals. These beneficial effects on glucose metabolism were associated with increased AMP kinase and hexokinase activities, as well as elevated levels of GLUT4 and myocyte enhancer factor-2 proteins A and D in skeletal muscle. These results suggest that UCP-H mice have a mitochondrial myopathy due to depleted energy stores sufficient to compromise growth and impair muscle function. Enhanced skeletal muscle glucose transport in this setting suggests that excess intramyocellular lipid and mitochondrial dysfunction are not sufficient to cause insulin resistance in mice.

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Overexpression of protein kinase STK25 in mice exacerbates ectopic lipid accumulation, mitochondrial dysfunction and insulin resistance in skeletal muscle

Diabetologia ◽

10.1007/s00125-016-4171-5 ◽

2016 ◽

Vol 60 (3) ◽

pp. 553-567 ◽

Cited By ~ 19

Author(s):

Urszula Chursa ◽

Esther Nuñez-Durán ◽

Emmelie Cansby ◽

Manoj Amrutkar ◽

Silva Sütt ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Protein Kinase ◽

Mitochondrial Dysfunction ◽

Lipid Accumulation

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Impaired Glycogen Synthase Activity and Mitochondrial Dysfunction in Skeletal Muscle: Markers or Mediators of Insulin Resistance in Type 2 Diabetes?

Current Diabetes Reviews ◽

10.2174/1573399810602040375 ◽

2006 ◽

Vol 2 (4) ◽

pp. 375-395 ◽

Cited By ~ 41

Author(s):

Bentham Science Publisher Bentham Science Publisher

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Mitochondrial Dysfunction ◽

Glycogen Synthase ◽

Glycogen Synthase Activity

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14-Deoxy-11,12-Didehydroandrographolide Ameliorates Glucose Intolerance Enhancing the LKB1/AMPKα/TBC1D1/GLUT4 Signaling Pathway and Inducing GLUT4 Expression in Myotubes and Skeletal Muscle of Obese Mice

The American Journal of Chinese Medicine ◽

10.1142/s0192415x21500695 ◽

2021 ◽

pp. 1-19

Author(s):

Chih-Chieh Chen ◽

Chong-Kuei Lii ◽

Chia-Wen Lo ◽

Yi-Hsueh Lin ◽

Ya-Chen Yang ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Uptake ◽

Signaling Pathway ◽

Nuclear Translocation ◽

Time Dependent ◽

Antidiabetic Activity ◽

C2c12 Myotubes ◽

Dependent Manner ◽

Compound C

14-Deoxy-11,12-didehydroandrographolide (deAND), a bioactive component of Andrographis paniculata, has antidiabetic activity. AMP-activated protein kinase (AMPK) regulates glucose transport and ameliorates insulin resistance. The aim of the present study was to investigate whether activation of AMPK is involved in the mechanism by which deAND ameliorates insulin resistance in muscles. deAND amounts up to 40 [Formula: see text]M dose-dependently activated phosphorylation of AMPK[Formula: see text] and TBC1D1 in C2C12 myotubes. In addition, deAND significantly activated phosphorylation of LKB1 at 6 h after treatment, and this activation was maintained up to 48 h. deAND increased glucose uptake at 18 h after treatment, and this increase was time dependent up to 72 h. Compound C, an inhibitor of AMPK, suppressed deAND-induced phosphorylation of AMPK[Formula: see text] and TBC1D1 and reversed the effect on glucose uptake. In addition, the expression of GLUT4 mRNA and protein in C2C12 myotubes was up-regulated by deAND in a time-dependent manner. Promotion of GLUT4 gene transcription was verified by a pGL3-GLUT4 (837 bp) reporter assay. deAND also increased the nuclear translocation of MEF-2A and PPAR[Formula: see text]. After 16 weeks of feeding, the high-fat diet (HFD) inhibited phosphorylation of AMPK[Formula: see text] and TBC1D1 in skeletal muscle of obese C57BL/6JNarl mice, and deactivation of AMPK[Formula: see text] and TBC1D1 by the HFD was abolished by deAND supplementation. Supplementation with deAND significantly promoted membrane translocation of GLUT4 compared with the HFD group. Supplementation also significantly increased GLUT4 mRNA and protein expression in skeletal muscle compared with the HFD group. The hypoglycemic effects of deAND are likely associated with activation of the LKB1/AMPK[Formula: see text]/TBC1D1/GLUT4 signaling pathway and stimulation of MEF-2A- and PPAR[Formula: see text]-dependent GLUT4 gene expression, which account for the glucose uptake into skeletal muscle and lower blood glucose levels.

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Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00159.2011 ◽

2012 ◽

Vol 302 (6) ◽

pp. E731-E739 ◽

Cited By ~ 81

Author(s):

Maria H. Holmström ◽

Eduardo Iglesias-Gutierrez ◽

Juleen R. Zierath ◽

Pablo M. Garcia-Roves

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Mitochondrial Dysfunction ◽

Mitochondrial Respiration ◽

Mitochondrial Dynamics ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Respiratory Capacity ◽

Tissue Specific ◽

Mitochondrial Respiratory

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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Mitochondria-associated ER membranes in glucose homeostasis and insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00271.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. E1053-E1060

Author(s):

Logan K. Townsend ◽

Henver S. Brunetta ◽

Marcelo A. S. Mori

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Endoplasmic Reticulum ◽

Adipose Tissue ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Glucose Homeostasis ◽

Calcium Homeostasis ◽

Adenine Nucleotides ◽

Current Controversy

Obesity and insulin resistance (IR) are associated with endoplasmic reticulum (ER) stress and mitochondrial dysfunction in several tissues. Although for many years mitochondrial and ER function were studied separately, these organelles also connect to produce interdependent functions. Communication occurs at mitochondria-associated ER membranes (MAMs) and regulates lipid and calcium homeostasis, apoptosis, and the exchange of adenine nucleotides, among other things. Recent evidence suggests that MAMs contribute to organelle, cellular, and systemic metabolism. In obesity and IR models, metabolic tissues such as the liver, skeletal muscle, pancreas, and adipose tissue present alterations in MAM structure or function. The purpose of this mini review is to highlight the MAM disruptions that occur in each tissue during obesity and IR and its relationship with glucose homeostasis and IR. We also discuss the current controversy that surrounds MAMs’ role in the development of IR.

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Palmitate Induced Mitochondrial Deoxyribonucleic Acid Damage and Apoptosis in L6 Rat Skeletal Muscle Cells

Endocrinology ◽

10.1210/en.2006-0998 ◽

2007 ◽

Vol 148 (1) ◽

pp. 293-299 ◽

Cited By ~ 93

Author(s):

L. I. Rachek ◽

S. I. Musiyenko ◽

S. P. LeDoux ◽

G. L. Wilson

Keyword(s):

Insulin Resistance ◽

Reactive Oxygen Species ◽

Skeletal Muscle ◽

Fatty Acid ◽

Free Fatty Acid ◽

Mitochondrial Dysfunction ◽

No Synthase ◽

Oxygen Species ◽

Mtdna Damage ◽

L6 Myotubes

A major characteristic of type 2 diabetes mellitus (T2DM) is insulin resistance in skeletal muscle. A growing body of evidence indicates that oxidative stress that results from increased production of reactive oxygen species and/or reactive nitrogen species leads to insulin resistance, tissue damage, and other complications observed in T2DM. It has been suggested that muscular free fatty acid accumulation might be responsible for the mitochondrial dysfunction and insulin resistance seen in T2DM, although the mechanisms by which increased levels of free fatty acid lead to insulin resistance are not well understood. To help resolve this situation, we report that saturated fatty acid palmitate stimulated the expression of inducible nitric oxide (NO) synthase and the production of reactive oxygen species and NO in L6 myotubes. Additionally, palmitate caused a significant dose-dependent increase in mitochondrial DNA (mtDNA) damage and a subsequent decrease in L6 myotube viability and ATP levels at concentrations as low as 0.5 mm. Furthermore, palmitate induced apoptosis, which was detected by DNA fragmentation, caspase-3 cleavage, and cytochrome c release. N-acetyl cysteine, a precursor compound for glutathione formation, aminoguanidine, an inducible NO synthase inhibitor, and 5,10,15,20-tetrakis(4-sulphonatophenyl) porphyrinato iron (III), a peroxynitrite inhibitor, all prevented palmitate-induced mtDNA damage and diminished palmitate-induced cytotoxicity. We conclude that exposure of L6 myotubes to palmitate induced mtDNA damage and triggered mitochondrial dysfunction, which caused apoptosis. Additionally, our findings indicate that palmitate-induced mtDNA damage and cytotoxicity in skeletal muscle cells were caused by overproduction of peroxynitrite.

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The Mitochondrial Proteomic Signatures of Human Skeletal Muscle Linked to Insulin Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms21155374 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5374 ◽

Cited By ~ 1

Author(s):

Rikke Kruse ◽

Navid Sahebekhtiari ◽

Kurt Højlund

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Mitochondrial Dysfunction ◽

Human Skeletal Muscle ◽

Metabolic Disorders ◽

Muscle Protein ◽

Protein Profiling ◽

Muscle Mitochondria ◽

Mitochondrial Proteome ◽

Complex Disorders

Introduction: Mitochondria are essential in energy metabolism and cellular survival, and there is growing evidence that insulin resistance in chronic metabolic disorders, such as obesity, type 2 diabetes (T2D), and aging, is linked to mitochondrial dysfunction in skeletal muscle. Protein profiling by proteomics is a powerful tool to investigate mechanisms underlying complex disorders. However, despite significant advances in proteomics within the past two decades, the technologies have not yet been fully exploited in the field of skeletal muscle proteome. Area covered: Here, we review the currently available studies characterizing the mitochondrial proteome in human skeletal muscle in insulin-resistant conditions, such as obesity, T2D, and aging, as well as exercise-mediated changes in the mitochondrial proteome. Furthermore, we outline technical challenges and limitations and methodological aspects that should be considered when planning future large-scale proteomics studies of mitochondria from human skeletal muscle. Authors’ view: At present, most proteomic studies of skeletal muscle or isolated muscle mitochondria have demonstrated a reduced abundance of proteins in several mitochondrial biological processes in obesity, T2D, and aging, whereas the beneficial effects of exercise involve an increased content of muscle proteins involved in mitochondrial metabolism. Powerful mass-spectrometry-based proteomics now provides unprecedented opportunities to perform in-depth proteomics of muscle mitochondria, which in the near future is expected to increase our understanding of the complex molecular mechanisms underlying the link between mitochondrial dysfunction and insulin resistance in chronic metabolic disorders.

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