Skeletal Muscle Microvascular Dysfunction in Obesity-Related Insulin Resistance: Pathophysiological Mechanisms and Therapeutic Perspectives

Obesity is a worrisomely escalating public health problem globally and one of the leading causes of morbidity and mortality from noncommunicable disease. The epidemiological link between obesity and a broad spectrum of cardiometabolic disorders has been well documented; however, the underlying pathophysiological mechanisms are only partially understood, and effective treatment options remain scarce. Given its critical role in glucose metabolism, skeletal muscle has increasingly become a focus of attention in understanding the mechanisms of impaired insulin function in obesity and the associated metabolic sequalae. We examined the current evidence on the relationship between microvascular dysfunction and insulin resistance in obesity. A growing body of evidence suggest an intimate and reciprocal relationship between skeletal muscle microvascular and glucometabolic physiology. The obesity phenotype is characterized by structural and functional changes in the skeletal muscle microcirculation which contribute to insulin dysfunction and disturbed glucose homeostasis. Several interconnected etiologic molecular mechanisms have been suggested, including endothelial dysfunction by several factors, extracellular matrix remodelling, and induction of oxidative stress and the immunoinflammatory phenotype. We further correlated currently available pharmacological agents that have deductive therapeutic relevance to the explored pathophysiological mechanisms, highlighting a potential clinical perspective in obesity treatment.

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-00167 ◽

2019 ◽

Vol 104 (11) ◽

pp. 5372-5381 ◽

Cited By ~ 12

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.

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

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.773 ◽

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.

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CD44 contributes to hyaluronan-mediated insulin resistance in skeletal muscle of high-fat-fed C57BL/6 mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00215.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. E973-E983 ◽

Cited By ~ 3

Author(s):

Annie Hasib ◽

Chandani K. Hennayake ◽

Deanna P. Bracy ◽

Aimée R. Bugler-Lamb ◽

Louise Lantier ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

High Fat Diet ◽

Critical Role ◽

Chow Diet ◽

Wild Type ◽

High Fat ◽

Insulin Resistant ◽

Beneficial Effects

Extracellular matrix hyaluronan is increased in skeletal muscle of high-fat-fed insulin-resistant mice, and reduction of hyaluronan by PEGPH20 hyaluronidase ameliorates diet-induced insulin resistance (IR). CD44, the main hyaluronan receptor, is positively correlated with type 2 diabetes. This study determines the role of CD44 in skeletal muscle IR. Global CD44-deficient ( cd44−/−) mice and wild-type littermates ( cd44+/+) were fed a chow diet or 60% high-fat diet for 16 wk. High-fat-fed cd44−/− mice were also treated with PEGPH20 to evaluate its CD44-dependent action. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp (ICv). High-fat feeding increased muscle CD44 protein expression. In the absence of differences in body weight and composition, despite lower clamp insulin during ICv, the cd44−/− mice had sustained glucose infusion rate (GIR) regardless of diet. High-fat diet-induced muscle IR as evidenced by decreased muscle glucose uptake (Rg) was exhibited in cd44+/+ mice but absent in cd44−/− mice. Moreover, gastrocnemius Rg remained unchanged between genotypes on chow diet but was increased in high-fat-fed cd44−/− compared with cd44+/+ when normalized to clamp insulin concentrations. Ameliorated muscle IR in high-fat-fed cd44−/− mice was associated with increased vascularization. In contrast to previously observed increases in wild-type mice, PEGPH20 treatment in high-fat-fed cd44−/− mice did not change GIR or muscle Rg during ICv, suggesting a CD44-dependent action. In conclusion, genetic CD44 deletion improves muscle IR, and the beneficial effects of PEGPH20 are CD44-dependent. These results suggest a critical role of CD44 in promoting hyaluronan-mediated muscle IR, therefore representing a potential therapeutic target for diabetes.

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

Endocrinology ◽

10.1210/en.2015-2027 ◽

2016 ◽

Vol 157 (6) ◽

pp. 2259-2269 ◽

Cited By ~ 33

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.

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PPARγExpression and Function in Mycobacterial Infection: Roles in Lipid Metabolism, Immunity, and Bacterial Killing

PPAR Research ◽

10.1155/2012/383829 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 52

Author(s):

Patricia E. Almeida ◽

Alan Brito Carneiro ◽

Adriana R. Silva ◽

Patricia T. Bozza

Keyword(s):

Molecular Mechanisms ◽

Critical Role ◽

Mycobacterial Infection ◽

Receptor Activation ◽

Host Cells ◽

Current Evidence ◽

Peroxisome Proliferator ◽

Bacterial Killing ◽

Peroxisome Proliferator Activated Receptor ◽

And Function

Tuberculosis continues to be a global health threat, with drug resistance and HIV coinfection presenting challenges for its control.Mycobacterium tuberculosis, the etiological agent of tuberculosis, is a highly adapted pathogen that has evolved different strategies to subvert the immune and metabolic responses of host cells. Although the significance of peroxisome proliferator-activated receptor gamma (PPARγ) activation by mycobacteria is not fully understood, recent findings are beginning to uncover a critical role for PPARγduring mycobacterial infection. Here, we will review the molecular mechanisms that regulate PPARγexpression and function during mycobacterial infection. Current evidence indicates that mycobacterial infection causes a time-dependent increase in PPARγexpression through mechanisms that involve pattern recognition receptor activation. Mycobacterial triggered increased PPARγexpression and activation lead to increased lipid droplet formation and downmodulation of macrophage response, suggesting that PPARγexpression might aid the mycobacteria in circumventing the host response acting as an escape mechanism. Indeed, inhibition of PPARγenhances mycobacterial killing capacity of macrophages, suggesting a role of PPARγin favoring the establishment of chronic infection. Collectively, PPARγis emerging as a regulator of tuberculosis pathogenesis and an attractive target for the development of adjunctive tuberculosis therapies.

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Oleate Blocks Palmitate-Induced Abnormal Lipid Distribution, Endoplasmic Reticulum Expansion and Stress, and Insulin Resistance in Skeletal Muscle

Endocrinology ◽

10.1210/en.2010-1369 ◽

2011 ◽

Vol 152 (6) ◽

pp. 2206-2218 ◽

Cited By ~ 98

Author(s):

Gong Peng ◽

Linghai Li ◽

Yanbo Liu ◽

Jing Pu ◽

Shuyan Zhang ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Fatty Acids ◽

Endoplasmic Reticulum ◽

Insulin Sensitivity ◽

Er Stress ◽

Molecular Mechanisms ◽

Dietary Fatty Acids ◽

Akt Phosphorylation ◽

Stress Relieving

Pathological elevation of plasma fatty acids reduces insulin sensitivity. Although several regulation pathways have been reported, the molecular mechanisms of insulin sensitivity remain elusive, especially in skeletal muscle where most glucose is consumed. This study focuses on how two major dietary fatty acids affect insulin signaling in skeletal muscle cells. Palmitic acid (PA) not only reduced insulin-stimulated phosphorylation of Akt but also induced endoplasmic reticulum (ER) expansion and ER stress. Relieving ER stress using 4-phenyl butyric acid blocked PA-mediated protein kinase R-like ER kinase phosphorylation and ER expansion and reversed the inhibitory effect of PA on insulin-stimulated Akt phosphorylation. Importantly, oleic acid (OA) could also recover PA-reduced Akt phosphorylation and abolish both PA-mediated ER expansion and ER stress. The competition between these two fatty acids was further verified in rat skeletal muscle using venous fatty acid infusion. 3H-labeled PA was converted mainly to active lipids (phospholipids and diacylglycerol) in the absence of OA, but to triacylglycerol in the presence of OA. Subcellular triacylglycerol and adipocyte differentiation-related protein from PA-treated cells cofractionated with the ER in the absence of OA but switched to the low-density fraction in the presence of OA. Taken together, these data suggest that the PA-mediated lipid composition and localization may cause ER expansion and consequently cause ER stress and insulin resistance in skeletal muscle.

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Role of proinflammatory cytokines and growth factors in skeletal muscle regeneration

Medycyna Weterynaryjna ◽

10.21521/mw.5551 ◽

2016 ◽

Vol 72 (8) ◽

pp. 472-478

Author(s):

Marta Milewska ◽

Katarzyna Grzelkowska-Kowalczyk

Keyword(s):

Skeletal Muscle ◽

Growth Factors ◽

Proinflammatory Cytokines ◽

Muscle Regeneration ◽

Molecular Mechanisms ◽

Critical Role ◽

Muscle Fibers ◽

Skeletal Muscle Regeneration ◽

Functional Efficiency

Skeletal muscle healing after injury can be divided into three distinct but overlapping phases. The destruction phase is characterized by rupture followed by necrosis of muscle fibers, formation of hematoma and inflammatory reaction. During the repair phase a necrotic tissue is phagocyted by macrophages, muscle fibers are regenerating and connective tissue scars are formed. The remodeling phase concerns the period when regenerating muscle fibers mature, scar contraction and reorganization occurs and the muscle recovers its functional efficiency. Proinflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and growth factors (FGF, IGF, TGF-β, HGF) play a critical role in all phases of muscle repair. Moreover, chemokines expressed at early stages of myogenesis can regulate the survival and proliferation of myoblasts. Chemokines expressed in vivo in muscle cells can directly influence myogenesis, but can also act in a paracrine manner by recruiting the immune cells (macrophages) to injured skeletal muscles, which is crucial for the regeneration process. Identification of molecules regulating myogenesis, like cytokines, chemokines and growth factors, contributes to the exploration of molecular mechanisms that can improve muscle regeneration after injury, diseases, surgery and increase the effectiveness of cell transplantation.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22179327 ◽

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.

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Alterations in the early steps of the insulin-signaling system in skeletal muscle of GH-transgenic mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.277.3.e447 ◽

1999 ◽

Vol 277 (3) ◽

pp. E447-E454 ◽

Cited By ~ 9

Author(s):

Fernando P. Dominici ◽

Debora Cifone ◽

Andrzej Bartke ◽

Daniel Turyn

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Transgenic Mice ◽

Tyrosine Phosphorylation ◽

Insulin Signaling ◽

Molecular Mechanisms ◽

Kinase Activity ◽

Signaling System ◽

Phosphorylation State ◽

Gh Excess

Growth hormone (GH) excess is associated with insulin resistance, but the molecular mechanisms of this association are poorly understood. In the current work, we have examined the consequences of exposure to high GH levels on the early steps of the insulin-signaling system in the muscle of bovine (b) GH-transgenic mice. The protein content and the tyrosine phosphorylation state of the insulin receptor (IR), the IR substrate-1 (IRS-1), the association between IRS-1 and the p85 subunit of phosphatidylinositol (PI) 3-kinase, and the phosphotyrosine-derived PI 3-kinase activity in this tissue were studied. We found that in skeletal muscle of bGH-transgenic mice, exposure to high circulating GH levels results in 1) reduced IR abundance, 2) reduced IR tyrosine phosphorylation, 3) reduced efficiency of IRS-1 tyrosine phosphorylation, and 4) defective activation of PI 3-kinase by insulin. These alterations may be related to the insulin resistance exhibited by these animals.

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Molecular Mechanisms of Glucocorticoid-Induced Insulin Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms22020623 ◽

2021 ◽

Vol 22 (2) ◽

pp. 623

Author(s):

Carine Beaupere ◽

Alexandrine Liboz ◽

Bruno Fève ◽

Bertrand Blondeau ◽

Ghislaine Guillemain

Keyword(s):

Insulin Resistance ◽

Molecular Mechanisms ◽

Cell Mass ◽

Beta Cell Mass ◽

New Drugs ◽

Therapeutic Benefits ◽

Cardiometabolic Disorders ◽

Paradoxical Effects ◽

Metabolic Imbalance

Glucocorticoids (GCs) are steroids secreted by the adrenal cortex under the hypothalamic-pituitary-adrenal axis control, one of the major neuro-endocrine systems of the organism. These hormones are involved in tissue repair, immune stability, and metabolic processes, such as the regulation of carbohydrate, lipid, and protein metabolism. Globally, GCs are presented as ‘flight and fight’ hormones and, in that purpose, they are catabolic hormones required to mobilize storage to provide energy for the organism. If acute GC secretion allows fast metabolic adaptations to respond to danger, stress, or metabolic imbalance, long-term GC exposure arising from treatment or Cushing’s syndrome, progressively leads to insulin resistance and, in fine, cardiometabolic disorders. In this review, we briefly summarize the pharmacological actions of GC and metabolic dysregulations observed in patients exposed to an excess of GCs. Next, we describe in detail the molecular mechanisms underlying GC-induced insulin resistance in adipose tissue, liver, muscle, and to a lesser extent in gut, bone, and brain, mainly identified by numerous studies performed in animal models. Finally, we present the paradoxical effects of GCs on beta cell mass and insulin secretion by the pancreas with a specific focus on the direct and indirect (through insulin-sensitive organs) effects of GCs. Overall, a better knowledge of the specific action of GCs on several organs and their molecular targets may help foster the understanding of GCs’ side effects and design new drugs that possess therapeutic benefits without metabolic adverse effects.

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