Insulin Resistance Mediates Crosstalk between Skeletal Muscle and the Heart to Prevent Cardiac Dysfunction

AbstractObesity and type 2 diabetes milieus (T2DM) are the leading causes of cardiovascular morbidity and mortality. Although insulin resistance is believed to underlie these disorders, a paradox exists that obese patients with cardiovascular diseases have better prognoses relative to leaner patients with the same diagnoses, whereas improvement of insulin sensitivity by thiazolidines significantly increases the risk of heart failure in T2DM patients. Using mice with skeletal muscle-specific deletion of the insulin receptor gene (MIRKO), we resolved this dilemma by demonstrating that insulin resistance in the skeletal muscle prevents myocardial hypertrophy and dysfunction in response to diet-induced obesity. In spite of aggregating obesity, insulin resistance selectively protected the heart, but not other metabolic tissues, from mitochondrial dysfunction and insulin resistance in MIRKO mice, leading to significant attenuation of inflammation and apoptosis of cardiomyocytes. Together, our findings revealed an unexpected role of insulin resistance as a double edge sword, calling for reevaluation of ongoing efforts for targeting insulin resistance for the treatment of metabolic diseases.Significance statementInsulin resistance is commonly recognized as one of the major causes of T2DM and other aging-related chronic diseases. However, cumulative efforts in targeting insulin resistance for the treatment of T2DM and other metabolic disorders have not met with great success due to unwanted side effects on heart failure. Here we report that insulin resistance in skeletal muscle is a double edge sword. On one hand, insulin resistance in skeletal muscle aggregates obesity and its related metabolic syndromes, and on the other it protects the heart from the development of myocardial hypertrophy, dysfunction, and apoptosis in response to DIO. Our findings call for reevaluation of the ongoing strategies in targeting insulin resistance as a novel treatment for T2DM and other metabolic diseases.

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Abstract 17649: Inhibition of Src Homology 2 Domain-containing Phosphatase 1 (SHP-1) Increases Insulin Sensitivity in High-fat Diet-induced Insulin Resistant C57black6 Mice

Circulation ◽

10.1161/circ.130.suppl_2.17649 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Janine Krüger ◽

Markus Dagnell ◽

Philipp Stawowy ◽

Evren Caglayan ◽

Arne Östman ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Body Weight ◽

Glucose Tolerance ◽

High Fat Diet ◽

Metabolic Diseases ◽

High Fat ◽

Insulin Resistant ◽

Cardiovascular Morbidity And Mortality

Background: Insulin resistance plays a crucial role in the development of type 2 diabetes, and exerts great impact on vascular inflammation and remodeling. At the molecular level a post-insulin receptor (IR) defect in insulin signaling has been suggested to contribute to insulin resistance. IR signaling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). The precise role of PTPs in insulin resistance, however, has not been explored. Results: Male C57BL/6J mice were fed a high-fat diet (HFD, 60% kcal from fat) to induce insulin resistance, or a low-fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD mice were treated with PTP-inhibitors for additional 6 weeks. Mice under HFD exhibited a significant increase in body weight as well as decreased respiratory quotient and adiponectin levels, and were characterized by impaired insulin- and glucose tolerance. Organ-based gene expression analyses in insulin-resistant mice demonstrated upregulation of SHP-1, PTP1B, LAR, and DEP-1 in insulin-sensitive organs. SHP-1 was further explored in vitro. Insulin stimulation in murine liver cells induced site-selective hyper-phosphorylation at IR tyrosine-sites Y1158, and Y1361 after inhibition of SHP-1. Furthermore, SHP-1 impairment time-dependently enhanced insulin-induced Akt- and Erk-phosphorylation, and resulted in elevated glucose uptake in skeletal muscle cells. Administration of a SHP-1 inhibitor (Sodium Stibogluconate) and a brought pan-PTP inhibitor (BMOV) in HFD mice led to improvement of both insulin- and glucose tolerance. In accordance, PTP-activity was significantly impaired in epididymal fat, skeletal muscle, and liver under BMOV treatment, being confirmed by reduced ex vivo dephosphorylation of a radioactive labelled peptide (AEEEIYGEFEAKKKK). Finally, BMOV- and SHP-1 treatment also resulted in reduced body weight. Conclusions: IR-antagonizing PTPs were organ-specifically regulated in insulin resistance. The results indicate a central role of PTPs and, in particular, of SHP-1 as endogenous antagonists of the IR. Taken together targeting PTPs led to beneficial effects in insulin resistance, and may thus improve metabolic diseases as well as cardiovascular morbidity and mortality.

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Insulin Resistance in Skeletal Muscle Selectively Protects the Heart in Response to Metabolic Stress

10.2337/figshare.14903118.v1 ◽

2021 ◽

Author(s):

Dandan Jia ◽

Jun Zhang ◽

Xueling Liu ◽

John-Paul Andersen ◽

Zhenjun Tian ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Metabolic Diseases ◽

Metabolic Stress ◽

Metabolic Reprogramming ◽

Myocardial Inflammation ◽

Common Belief ◽

Insulin Sensitizer ◽

Cardiovascular Morbidity And Mortality ◽

Myocardial Insulin Resistance

<a>Obesity and type 2 diabetes mellitus (T2DM) are the leading causes of cardiovascular morbidity and mortality. Although insulin resistance is believed to underlie these disorders, </a><a>anecdotal evidence contradicts this common belief. Accordingly, obese patients with cardiovascular disease have better prognoses relative to leaner patients with the same diagnoses, whereas treatment of T2DM patients with thiazolidines, one of the popular insulin sensitizer drugs, significantly increases the risk of heart failure. </a>Using mice with skeletal muscle-specific <a>ablation of the insulin receptor </a>gene (MIRKO), we addressed this paradox by demonstrating that insulin signaling in skeletal muscles specifically mediated crosstalk with the heart, but not other metabolic tissues, to prevent cardiac dysfunction in response to metabolic stress. Despite severe hyperinsulinemia and aggregating obesity, MIRKO mice were protected from myocardial insulin resistance, mitochondrial dysfunction, and metabolic reprogramming in response to diet-induced obesity (DIO). Consequently, the MIRKO mice were also protected from myocardial inflammation, cardiomyopathy, and left ventricle dysfunction. Together, our findings suggest that insulin resistance in skeletal muscle functions as a double-edged sword in metabolic diseases.

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Insulin Resistance in Skeletal Muscle Selectively Protects the Heart in Response to Metabolic Stress

10.2337/figshare.14903118 ◽

2021 ◽

Author(s):

Dandan Jia ◽

Jun Zhang ◽

Xueling Liu ◽

John-Paul Andersen ◽

Zhenjun Tian ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Metabolic Diseases ◽

Metabolic Stress ◽

Metabolic Reprogramming ◽

Myocardial Inflammation ◽

Common Belief ◽

Insulin Sensitizer ◽

Cardiovascular Morbidity And Mortality ◽

Myocardial Insulin Resistance

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Intramyocellular fat storage in metabolic diseases

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2015-0045 ◽

2016 ◽

Vol 26 (1) ◽

Cited By ~ 3

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.

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Oxidative stress impairs insulin signal in skeletal muscle and causes insulin resistance in postinfarct heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01185.2009 ◽

2011 ◽

Vol 300 (5) ◽

pp. H1637-H1644 ◽

Cited By ~ 34

Author(s):

Yukihiro Ohta ◽

Shintaro Kinugawa ◽

Shouji Matsushima ◽

Taisuke Ono ◽

Mochamad A. Sobirin ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Signaling ◽

Glucose Transporter ◽

Diastolic Pressure ◽

Left Ventricular ◽

Serine Phosphorylation ◽

Glucose Transporter 4

Insulin resistance has been shown to occur as a consequence of heart failure. However, its exact mechanisms in this setting remain unknown. We have previously reported that oxidative stress is enhanced in the skeletal muscle from mice with heart failure after myocardial infarction (MI) ( 30 ). This study is aimed to investigate whether insulin resistance in postinfarct heart failure is due to the impairment of insulin signaling in the skeletal muscle caused by oxidative stress. Mice were divided into four groups: sham operated (sham); sham treated with apocynin, an inhibitor of NAD(P)H oxidase activation (10 mmol/l in drinking water); MI; and MI treated with apocynin. After 4 wk, intraperitoneal insulin tolerance tests were performed, and skeletal muscle samples were obtained for insulin signaling measurements. MI mice showed left ventricular dilation and dysfunction by echocardiography and increased left ventricular end-diastolic pressure and lung weight. The decrease in glucose level after insulin load significantly attenuated in MI compared with sham. Insulin-stimulated serine phosphorylation of Akt and glucose transporter-4 translocation were decreased in MI mice by 61 and 23%, respectively. Apocynin ameliorated the increase in oxidative stress and NAD(P)H oxidase activities measured by the lucigenin assay in the skeletal muscle after MI. It also improved insulin resistance and inhibited the decrease of Akt phosphorylation and glucose transporter-4 translocation. Insulin resistance was induced by the direct impairment of insulin signaling in the skeletal muscle from postinfarct heart failure, which was associated with the enhanced oxidative stress via NAD(P)H oxidase.

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(Pro)renin receptor in skeletal muscle is involved in the development of insulin resistance associated with postinfarct heart failure in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00449.2013 ◽

2014 ◽

Vol 307 (6) ◽

pp. E503-E514 ◽

Cited By ~ 23

Author(s):

Arata Fukushima ◽

Shintaro Kinugawa ◽

Shingo Takada ◽

Shouji Matsushima ◽

Mochamad Ali Sobirin ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Signaling ◽

Glucose Transporter ◽

Renin Angiotensin System ◽

Left Ventricular ◽

Serine Phosphorylation ◽

Superoxide Production

We previously reported that insulin resistance was induced by the impairment of insulin signaling in the skeletal muscle from heart failure (HF) via NAD(P)H oxidase-dependent oxidative stress. (Pro)renin receptor [(P)RR] is involved in the activation of local renin-angiotensin system and subsequent oxidative stress. We thus examined whether (P)RR inhibitor, handle region peptide (HRP), could ameliorate insulin resistance in HF after myocardial infarction (MI) by improving oxidative stress and insulin signaling in the skeletal muscle. C57BL6J mice were divided into four groups: sham operated (Sham, n = 10), Sham treated with HRP (Sham+HRP, 0.1 mg·kg−1·day−1, n = 10), MI operated (MI, n = 10), and MI treated with HRP (MI+HRP, 0.1 mg/kg/day, n = 10). After 4 wk, MI mice showed left ventricular dysfunction, which was not affected by HRP. (P)RR was upregulated in the skeletal muscle after MI (149% of sham, P < 0.05). The decrease in plasma glucose after insulin load was smaller in MI than in Sham (21 ± 2 vs. 44 ± 3%, P < 0.05), and was greater in MI+HRP (38 ± 2%, P < 0.05) than in MI. Insulin-stimulated serine phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle from MI by 48 and 49% of Sham, both of which were ameliorated in MI+HRP. Superoxide production and NAD(P)H oxidase activities were increased in MI, which was inhibited in MI+HRP. HRP ameliorated insulin resistance associated with HF by improving insulin signaling via the inhibition of NAD(P)H oxidase-induced superoxide production in the skeletal muscle. The (P)RR pathway is involved in the development of insulin resistance, at least in part, via the impairment of insulin signaling in the skeletal muscle from HF.

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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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RNA-sequencing analysis reveals the potential contribution of lncRNAs in palmitic acid-induced insulin resistance of skeletal muscle cells

Bioscience Reports ◽

10.1042/bsr20192523 ◽

2020 ◽

Vol 40 (1) ◽

Cited By ~ 1

Author(s):

Mei Han ◽

Lianghui You ◽

Yanting Wu ◽

Nan Gu ◽

Yan Wang ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Palmitic Acid ◽

Signaling Pathway ◽

Rna Sequencing ◽

Metabolic Diseases ◽

Muscle Cells ◽

Skeletal Muscle Cells ◽

C2c12 Myotubes ◽

Insulin Resistant

Abstract Insulin resistance (IR) has been considered as the common pathological basis and developmental driving force for most metabolic diseases. Long noncoding RNAs (lncRNAs) have emerged as pivotal regulators in modulation of glucose and lipid metabolism. However, the comprehensive profile of lncRNAs in skeletal muscle cells under the insulin resistant status and the possible biological effects of them were not fully studied. In this research, using C2C12 myotubes as cell models in vitro, deep RNA-sequencing was performed to profile lncRNAs and mRNAs between palmitic acid-induced IR C2C12 myotubes and control ones. The results revealed that a total of 144 lncRNAs including 70 up-regulated and 74 down-regulated (|fold change| > 2, q < 0.05) were significantly differentially expressed in palmitic acid-induced insulin resistant cells. In addition, functional annotation analysis based on the Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) databases revealed that the target genes of the differentially expressed lncRNAs were significantly enriched in fatty acid oxidation, lipid oxidation, PPAR signaling pathway, and insulin signaling pathway. Moreover, Via qPCR, most of selected lncRNAs in myotubes and db/db mice skeletal muscle showed the consistent expression trends with RNA-sequencing. Co-expression analysis also explicated the key lncRNA–mRNA interactions and pointed out a potential regulatory network of candidate lncRNA ENSMUST00000160839. In conclusion, the present study extended the skeletal muscle lncRNA database and provided novel potential regulators for future genetic and molecular studies on insulin resistance, which is helpful for prevention and treatment of the related metabolic diseases.

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