scholarly journals Exploring the Role of Skeletal Muscle in Insulin Resistance: Lessons from Cultured Cells to Animal Models

2021 ◽  
Vol 22 (17) ◽  
pp. 9327
Author(s):  
Alessandra Feraco ◽  
Stefania Gorini ◽  
Andrea Armani ◽  
Elisabetta Camajani ◽  
Manfredi Rizzo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Animal Models ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Cultured Cells ◽  
Endocrine Function ◽  
Glucose Disposal ◽  
Skeletal Muscle Function ◽  
Vital Functions

Skeletal muscle is essential to maintain vital functions such as movement, breathing, and thermogenesis, and it is now recognized as an endocrine organ. Muscles release factors named myokines, which can regulate several physiological processes. Moreover, skeletal muscle is particularly important in maintaining body homeostasis, since it is responsible for more than 75% of all insulin-mediated glucose disposal. Alterations of skeletal muscle differentiation and function, with subsequent dysfunctional expression and secretion of myokines, play a key role in the pathogenesis of obesity, type 2 diabetes, and other metabolic diseases, finally leading to cardiometabolic complications. Hence, a deeper understanding of the molecular mechanisms regulating skeletal muscle function related to energy metabolism is critical for novel strategies to treat and prevent insulin resistance and its cardiometabolic complications. This review will be focused on both cellular and animal models currently available for exploring skeletal muscle metabolism and endocrine function.

scholarly journals Kinome Profiling Reveals Abnormal Activity of Kinases in Skeletal Muscle From Adults With Obesity and Insulin Resistance

2019 ◽  
Vol 105 (3) ◽  
pp. 644-659
Author(s):  
Yue Qi ◽  
Xiangmin Zhang ◽  
Berhane Seyoum ◽  
Zaher Msallaty ◽  
Abdullah Mallisho ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Kinases ◽  
Insulin Signaling ◽  
Human Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Kinase Activity ◽  
Metabolic Diseases ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance

Abstract Context Obesity-related insulin resistance (OIR) is one of the main contributors to type 2 diabetes and other metabolic diseases. Protein kinases are implicated in insulin signaling and glucose metabolism. Molecular mechanisms underlying OIR involving global kinase activities remain incompletely understood. Objective To investigate abnormal kinase activity associated with OIR in human skeletal muscle. Design Utilization of stable isotopic labeling-based quantitative proteomics combined with affinity-based active enzyme probes to profile in vivo kinase activity in skeletal muscle from lean control (Lean) and OIR participants. Participants A total of 16 nondiabetic adults, 8 Lean and 8 with OIR, underwent hyperinsulinemic-euglycemic clamp with muscle biopsy. Results We identified the first active kinome, comprising 54 active protein kinases, in human skeletal muscle. The activities of 23 kinases were different in OIR muscle compared with Lean muscle (11 hyper- and 12 hypo-active), while their protein abundance was the same between the 2 groups. The activities of multiple kinases involved in adenosine monophosphate–activated protein kinase (AMPK) and p38 signaling were lower in OIR compared with Lean. On the contrary, multiple kinases in the c-Jun N-terminal kinase (JNK) signaling pathway exhibited higher activity in OIR vs Lean. The kinase-substrate–prediction based on experimental data further confirmed a potential downregulation of insulin signaling (eg, inhibited phosphorylation of insulin receptor substrate-1 and AKT1/2). Conclusions These findings provide a global view of the kinome activity in OIR and Lean muscle, pinpoint novel specific impairment in kinase activities in signaling pathways important for skeletal muscle insulin resistance, and may provide potential drug targets (ie, abnormal kinase activities) to prevent and/or reverse skeletal muscle insulin resistance in humans.

scholarly journals Molecular Mechanisms of Insulin Resistance in Polycystic Ovary Syndrome: Unraveling the Conundrum in Skeletal Muscle?

2019 ◽  
Vol 104 (11) ◽  
pp. 5372-5381 ◽  
Author(s):  
Nigel K Stepto ◽  
Alba Moreno-Asso ◽  
Luke C McIlvenna ◽  
Kirsty A Walters ◽  
Raymond J Rodgers
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Polycystic Ovary Syndrome ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Polycystic Ovary ◽  
Evidence Synthesis ◽  
Basic Research ◽  
Future Research ◽  
Ovary Syndrome

Abstract Context Polycystic ovary syndrome (PCOS) is a common endocrine condition affecting 8% to 13% of women across the lifespan. PCOS affects reproductive, metabolic, and mental health, generating a considerable health burden. Advances in treatment of women with PCOS has been hampered by evolving diagnostic criteria and poor recognition by clinicians. This has resulted in limited clinical and basic research. In this study, we provide insights into the current and future research on the metabolic features of PCOS, specifically as they relate to PCOS-specific insulin resistance (IR), that may affect the most metabolically active tissue, skeletal muscle. Current Knowledge PCOS is a highly heritable condition, yet it is phenotypically heterogeneous in both reproductive and metabolic features. Human studies thus far have not identified molecular mechanisms of PCOS-specific IR in skeletal muscle. However, recent research has provided new insights that implicate energy-sensing pathways regulated via epigenomic and resultant transcriptomic changes. Animal models, while in existence, have been underused in exploring molecular mechanisms of IR in PCOS and specifically in skeletal muscle. Future Directions Based on the latest evidence synthesis and technologies, researchers exploring molecular mechanisms of IR in PCOS, specifically in muscle, will likely need to generate new hypothesis to be tested in human and animal studies. Conclusion Investigations to elucidate the molecular mechanisms driving IR in PCOS are in their early stages, yet remarkable advances have been made in skeletal muscle. Overall, investigations have thus far created more questions than answers, which provide new opportunities to study complex endocrine conditions.

Intramyocellular fat storage in metabolic diseases

2016 ◽  
Vol 26 (1) ◽  
Author(s):  
Claire Laurens ◽  
Cedric Moro
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Metabolic Diseases ◽  
Recent Literature ◽  
Lipid Storage ◽  
Muscle Lipid ◽  
The Past ◽  
Skeletal Muscle Lipid ◽  
Ectopic Lipid Storage

AbstractOver the past decades, obesity and its metabolic co-morbidities such as type 2 diabetes (T2D) developed to reach an endemic scale. However, the mechanisms leading to the development of T2D are still poorly understood. One main predictor for T2D seems to be lipid accumulation in “non-adipose” tissues, best known as ectopic lipid storage. A growing body of data suggests that these lipids may play a role in impairing insulin action in metabolic tissues, such as liver and skeletal muscle. This review aims to discuss recent literature linking ectopic lipid storage and insulin resistance, with emphasis on lipid deposition in skeletal muscle. The link between skeletal muscle lipid content and insulin sensitivity, as well as the mechanisms of lipid-induced insulin resistance and potential therapeutic strategies to alleviate lipotoxic lipid pressure in skeletal muscle will be discussed.

scholarly journals Novel Insights and Mechanisms of Lipotoxicity-Driven Insulin Resistance

2020 ◽  
Vol 21 (17) ◽  
pp. 6358 ◽  
Author(s):  
Benjamin Lair ◽  
Claire Laurens ◽  
Bram Van Den Bosch ◽  
Cedric Moro
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Acyl Chain ◽  
The Body ◽  
Glucose Disposal ◽  
Tissue Lipid ◽  
Lipid Species ◽  
Chain Composition

A large number of studies reported an association between elevated circulating and tissue lipid content and metabolic disorders in obesity, type 2 diabetes (T2D) and aging. This state of uncontrolled tissue lipid accumulation has been called lipotoxicity. It was later shown that excess lipid flux is mainly neutralized within lipid droplets as triglycerides, while several bioactive lipid species such as diacylglycerols (DAGs), ceramides and their derivatives have been mechanistically linked to the pathogenesis of insulin resistance (IR) by antagonizing insulin signaling and action in metabolic organs such as the liver and skeletal muscle. Skeletal muscle and the liver are the main sites of glucose disposal in the body and IR in these tissues plays a pivotal role in the development of T2D. In this review, we critically examine recent literature supporting a causal role of DAGs and ceramides in the development of IR. A particular emphasis is placed on transgenic mouse models with modulation of total DAG and ceramide pools, as well as on modulation of specific subspecies, in relation to insulin sensitivity. Collectively, although a wide number of studies converge towards the conclusion that both DAGs and ceramides cause IR in metabolic organs, there are still some uncertainties on their mechanisms of action. Recent studies reveal that subcellular localization and acyl chain composition are determinants in the biological activity of these lipotoxic lipids and should be further examined.

Prevention of skeletal muscle insulin resistance by dietary cod protein in high fat-fed rats

2001 ◽  
Vol 281 (1) ◽  
pp. E62-E71 ◽  
Author(s):  
Charles Lavigne ◽  
Frédéric Tremblay ◽  
Geneviève Asselin ◽  
Hélène Jacques ◽  
André Marette
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Amino Acids ◽  
Glucose Uptake ◽  
Soy Protein ◽  
Whole Body ◽  
Glucose Disposal ◽  
High Fat ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance

In the present study, we tested the hypothesis that fish protein may represent a key constituent of fish with glucoregulatory activity. Three groups of rats were fed a high-fat diet in which the protein source was casein, fish (cod) protein, or soy protein; these groups were compared with a group of chow-fed controls. High-fat feeding led to severe whole body and skeletal muscle insulin resistance in casein- or soy protein-fed rats, as assessed by the euglycemic clamp technique coupled with measurements of 2-deoxy-d-[3H]glucose uptake rates by individual tissues. However, feeding cod protein fully prevented the development of insulin resistance in high fat-fed rats. These animals exhibited higher rates of insulin-mediated muscle glucose disposal that were comparable to those of chow-fed rats. The beneficial effects of cod protein occurred without any reductions in body weight gain, adipose tissue accretion, or expression of tumor necrosis factor-α in fat and muscle. Moreover, L6 myocytes exposed to cod protein-derived amino acids showed greater rates of insulin-stimulated glucose uptake compared with cells incubated with casein- or soy protein-derived amino acids. These data demonstrate that feeding cod protein prevents obesity-induced muscle insulin resistance in high fat-fed obese rats at least in part through a direct action of amino acids on insulin-stimulated glucose uptake in skeletal muscle cells.

scholarly journals MON-647 Mechanisms of Insulin Resistance in Skeletal Muscle in Women with PCOS

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Alba Moreno-Asso ◽  
Luke C McIlvenna ◽  
Rhiannon K Patten ◽  
Andrew J McAinch ◽  
Raymond J Rodgers ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Reproductive Age ◽  
Whole Body ◽  
Dependent Manner ◽  
Cultured Myotubes ◽  
Tgfβ Superfamily

Abstract Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder affecting metabolic, reproductive and mental health of 8-13% of reproductive-age women. Insulin resistance (IR) appears to underpin the pathophysiology of PCOS and is present in approximately 85% of women with PCOS. This underlying IR has been identified as unique from, but synergistic with, obesity-induced IR (1). Skeletal muscle accounts for up to 85% of whole body insulin-stimulated glucose uptake, however, in PCOS this is reduced about 27% when assessed by hyperinsulinemic euglycemic clamp (2). Interestingly, this reduced insulin-stimulated glucose uptake observed in skeletal muscle tissue is not retained in cultured myotubes (3), suggesting that environmental factors may play a role in this PCOS-specific IR. Yet, the molecular mechanisms regulating IR remain unclear (4). Previous work suggested that Transforming Growth Factor Beta (TGFβ) superfamily ligands may be involved in the metabolic morbidity associated with PCOS (5). In this study, we investigated the effects of TGFβ1 (1, 5ng/ml), and the Anti-Müllerian hormone (AMH; 5, 10, 30ng/ml), a novel TGFβ superfamily ligand elevated in women with PCOS, as causal factors of IR in cultured myotubes from women with PCOS (n=10) and healthy controls (n=10). AMH negatively affected glucose uptake and insulin signalling increasing p-IRS1 (ser312) in a dose-dependent manner in myotubes from both women with and without PCOS. AMH did not appear to activate the canonical TGFβ/BMP signalling pathway. Conversely, TGFβ1 had an opposite effect in both PCOS and control myotubes cultures, decreasing phosphorylation of IRS1 (ser312) and enhancing glucose uptake via Smad2/3 signalling. In conclusion, these results suggest that AMH may play a role in skeletal muscle IR observed in PCOS, however, further research is required to elucidate its mechanisms of action and broader impact in this syndrome. References: (1) Stepto et al. Hum Reprod 2013 Mar;28(3):777-784. (2) Cassar et al. Hum Reprod 2016 Nov;31(11):2619-2631. (3) Corbould et al., Am J Physiol-Endoc 2005 May;88(5):E1047-54. (4) Stepto et al. J Clin Endocrinol Metab, 2019 Nov 1;104(11):5372-5381. (5) Raja-Khan et al. Reprod Sci 2014 Jan;21(1):20-31.

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 A Molecular and Whole Body Insight of the Mechanisms Surrounding Glucose Disposal and Insulin Resistance with Hypoxic Treatment in Skeletal Muscle

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
R. W. A. Mackenzie ◽  
P. Watt
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Control ◽  
Direct Action ◽  
Acute Hypoxia ◽  
Whole Body ◽  
Glucose Disposal ◽  
Hypoxic Exposure ◽  
Obstructive Sleep

Although the mechanisms are largely unidentified, the chronic or intermittent hypoxic patterns occurring with respiratory diseases, such as chronic pulmonary disease or obstructive sleep apnea (OSA) and obesity, are commonly associated with glucose intolerance. Indeed, hypoxia has been widely implicated in the development of insulin resistance either via the direct action on insulin receptor substrate (IRS) and protein kinase B (PKB/Akt) or indirectly through adipose tissue expansion and systemic inflammation. Yet hypoxia is also known to encourage glucose transport using insulin-dependent mechanisms, largely reliant on the metabolic master switch, 5′ AMP-activated protein kinase (AMPK). In addition, hypoxic exposure has been shown to improve glucose control in type 2 diabetics. The literature surrounding hypoxia-induced changes to glycemic control appears to be confusing and conflicting. How is it that the same stress can seemingly cause insulin resistance while increasing glucose uptake? There is little doubt that acute hypoxia increases glucose metabolism in skeletal muscle and does so using the same pathway as muscle contraction. The purpose of this review paper is to provide an insight into the mechanisms underpinning the observed effects and to open up discussions around the conflicting data surrounding hypoxia and glucose control.

scholarly journals CLOCK and BMAL1 Regulate Muscle Insulin Sensitivity via SIRT1 in Male Mice

Endocrinology ◽  
2016 ◽  
Vol 157 (6) ◽  
pp. 2259-2269 ◽  
Author(s):  
Jun Liu ◽  
Ben Zhou ◽  
Menghong Yan ◽  
Rui Huang ◽  
Yuangao Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Molecular Mechanisms ◽  
Ectopic Expression ◽  
Sirtuin 1 ◽  
C2c12 Myotubes ◽  
Constant Darkness ◽  
Circadian Misalignment ◽  
Mouse Skeletal Muscle

Circadian misalignment induces insulin resistance in both human and animal models, and skeletal muscle is the largest organ response to insulin. However, how circadian clock regulates muscle insulin sensitivity and the underlying molecular mechanisms are still largely unknown. Here we show circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (BMAL)-1, two core circadian transcription factors, are down-regulated in insulin-resistant C2C12 myotubes and mouse skeletal muscle. Furthermore, insulin signaling is attenuated in the skeletal muscle of ClockΔ19/Δ19 mice, and knockdown of CLOCK or BMAL1 by small interfering RNAs induces insulin resistance in C2C12 myotubes. Consistently, ectopic expression of CLOCK and BMAL1 improves insulin sensitivity in C2C12 myotubes. Moreover, CLOCK and BMAL1 regulate the expression of sirtuin 1 (SIRT1), an important regulator of insulin sensitivity, in C2C12 myotubes and mouse skeletal muscle, and two E-box elements in Sirt1 promoter are responsible for its CLOCK- and BMAL1-dependent transcription in muscle cells. Further studies show that CLOCK and BMAL1 regulate muscle insulin sensitivity through SIRT1. In addition, we find that BMAL1 and SIRT1 are decreased in the muscle of mice maintained in constant darkness, and resveratrol supplementation activates SIRT1 and improves insulin sensitivity. All these data demonstrate that CLOCK and BMAL1 regulate muscle insulin sensitivity via SIRT1, and activation of SIRT1 might be a potential valuable strategy to attenuate muscle insulin resistance related to circadian misalignment.

scholarly journals Mammalian Tribbles homolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance

2010 ◽  
Vol 298 (3) ◽  
pp. E565-E576 ◽  
Author(s):  
Jiarong Liu ◽  
Xuxia Wu ◽  
John L. Franklin ◽  
Joseph L. Messina ◽  
Helliner S. Hill ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Transporter ◽  
Vastus Lateralis ◽  
Glucose Deprivation ◽  
Muscle Cells ◽  
Diabetic Rats ◽  
Glucose Disposal ◽  
Insulin Resistant ◽  
Protein Levels

Tribbles homolog 3 (TRIB3) was found to inhibit insulin-stimulated Akt phosphorylation and modulate gluconeogenesis in rodent liver. Currently, we examined a role for TRIB3 in skeletal muscle insulin resistance. Ten insulin-sensitive, ten insulin-resistant, and ten untreated type 2 diabetic (T2DM) patients were metabolically characterized by hyperinsulinemic euglycemic glucose clamps, and biopsies of vastus lateralis were obtained. Skeletal muscle samples were also collected from rodent models including streptozotocin (STZ)-induced diabetic rats, db/db mice, and Zucker fatty rats. Finally, L6 muscle cells were used to examine regulation of TRIB3 by glucose, and stable cell lines hyperexpressing TRIB3 were generated to identify mechanisms underlying TRIB3-induced insulin resistance. We found that 1) skeletal muscle TRIB3 protein levels are significantly elevated in T2DM patients; 2) muscle TRIB3 protein content is inversely correlated with glucose disposal rates and positively correlated with fasting glucose; 3) skeletal muscle TRIB3 protein levels are increased in STZ-diabetic rats, db/db mice, and Zucker fatty rats; 4) stable TRIB3 hyperexpression in muscle cells blocks insulin-stimulated glucose transport and glucose transporter 4 (GLUT4) translocation and impairs phosphorylation of Akt, ERK, and insulin receptor substrate-1 in insulin signal transduction; and 5) TRIB3 mRNA and protein levels are increased by high glucose concentrations, as well as by glucose deprivation in muscle cells. These data identify TRIB3 induction as a novel molecular mechanism in human insulin resistance and diabetes. TRIB3 acts as a nutrient sensor and could mediate the component of insulin resistance attributable to hyperglycemia (i.e., glucose toxicity) in diabetes.

Sign in / Sign up

Export Citation Format

Share Document