Skeletal Muscle Extracellular Matrix Remodeling Research Articles

Link between insulin resistance and skeletal muscle extracellular matrix remodeling.

Skeletal muscle is the main metabolic tissue responsible for glucose homeostasis in the body. It is surrounded by the extracellular matrix (ECM) consisting of three layers: epimysium, perimysium, and endomysium. ECM plays an important role in the muscle, as it provides integrity and scaffolding cells. The observed disturbances in this structure are related to the abnormal remodeling of the ECM (through an increase in the concentration of its components). ECM rearrangement may impair insulin action by increasing the physical barrier to insulin transport and reducing insulin transport into muscle cells as well as by directly inhibiting insulin action through integrin signaling. Thus, improper ECM remodeling may contribute to the development of insulin resistance (IR) and related comorbidities. In turn, IR-associated conditions may further aggravate disturbances of ECM in skeletal muscle. This review describes the major components of the ECM that are necessary for its proper function. Particular attention was also paid to receptors (integrins) involved in the signaling of metabolic pathways. Finally, changes in ECM components in the context of clinical and animal studies are discussed. This article will help the reader to systematize knowledge related to the ECM and to better understand the relationship between ECM remodeling and IR, and its role in the pathogenesis of T2DM. The information in this article presents the concept of the role of ECM and its remodeling in the pathogenesis of IR, which may contribute to developing new therapeutic solutions.

Obesity impairs skeletal muscle repair through NID-1 mediated extracellular matrix remodeling by mesenchymal progenitors

Obesity triggers skeletal muscle physio-pathological alterations. However, the crosstalk between adipose tissue and myogenic cells remains poorly understood during obesity. We identified NID-1 among the adipose tissue secreted factors impairing myogenic potential of human myoblasts and murine muscle stem cells in vitro. Mice under High Fat Diet (HFD) displayed increased NID-1 expression in the skeletal muscle endomysium associated with intramuscular fat adipose tissue expansion and compromised muscle stem cell function. We show that NID-1 is highly secreted by skeletal muscle fibro-adipogenic/mesenchymal progenitors (FAPs) during obesity. We demonstrate that increased muscle NID-1 impairs muscle stem cells proliferation and primes the fibrogenic differentiation of FAPs, giving rise to an excessive deposition of extracellular matrix. Finally, we propose a model in which obesity leads to skeletal muscle extracellular matrix remodeling by FAPs, mediating the alteration of myogenic function by adipose tissue and highlighting the key role of NID-1 in the crosstalk between adipose tissue and skeletal muscle.

Insulin Resistance, Skeletal Muscle Extracellular Matrix Remodeling, And The Effect Of Exercise

Extracellular matrix (ECM) remodeling in skeletal muscle is a potential mechanism linking obesity with metabolic dysfunction. It is also a constructive feature of skeletal muscle adaptation to exercise training. PURPOSE: To test the hypothesis that skeletal muscle ECM remodeling associated with insulin resistance can be minimized by exercise training. METHODS: Six-week-old male C57/BL6J mice (n=48) were divided into two groups, high-fat (60% calories from fat) diet (HF, n=36) and normal chow-fed control (C, n=12) group. After 12 weeks of feeding, HF mice developed insulin resistance, as confirmed by insulin and glucose tolerance tests (ITT and GTT). HF mice were then randomly assigned to three groups: high-fat diet only group (HFS, n=12), high-fat diet + aerobic exercise group (HF+AE, n=12), high-fat diet + resistance training group (HF+RT, n=12). The HF+AE and HF+RT groups were subject to aerobic (treadmill running) and resistive (vertical ladder climbing) training, for 12 weeks. After training, gastrocnemius muscle was harvested and analyzed for ECM factors using immunohistochemistry, ECM PCR array, and western blotting. ANOVA was performed to test the significance of group differences at p<0.05. RESULTS: High-fat feeding induced higher deposition of collagens (COLI, III and IV) in the skeletal muscle of HFS group, and increased gene and protein expression of MMP3, CDH1, ITGAL and SELL and decreased the expression of TIMP3 in HFS group, as compared to group C. These changes were minimized even reversed by either aerobic or resistance exercise training (mRNA fold change relative to C in HF+AE and HF+RT vs. HFS: MMP3, 1.1 and 1.6 vs. 2.6; CDH1, 1.7 and 1.1 vs. 2.0; ITGAL, 1.9 and -1.0 vs. 2.0; SELL, 1.4 and 1.0 vs. 2.1; TIMP3, 1.2 and -1.0 vs. -1.2; p<0.05). These effects were accompanied by a significant improvement in insulin sensitivity (GTT AUC glucose in mmol/l x 120 min: C, 27.2±3.0; HFS, 39.7 ± 7.0; HF+AE, 32.4± 7.5; HF+RT, 30.3± 6.1; p<0.05). CONCLUSION: Both aerobic and resistive exercise training can minimize changes in skeletal muscle ECM associated with insulin resistance. Skeletal muscle ECM remodeling may play a significant role in mediating the metabolic benefits of exercise training. This study was supported by National Nature Science Foundation of China (31470060).

Implications of Skeletal Muscle Extracellular Matrix Remodeling in Metabolic Disorders: Diabetes Perspective.

The extracellular matrix (ECM) provides a scaffold for cells, controlling biological processes and providing structural as well as mechanical support to surrounding cells. Disruption of ECM homeostasis results in several pathological conditions. Skeletal muscle ECM is a complex network comprising collagens, proteoglycans, glycoproteins, and elastin. Recent therapeutic approaches targeting ECM remodeling have been extensively deliberated. Various ECM components are typically found to be augmented in the skeletal muscle of obese and/or diabetic humans. Skeletal muscle ECM remodeling is thought to be a feature of the pathogenic milieu allied with metabolic dysregulation, obesity, and eventual diabetes. This narrative review explores the current understanding of key components of skeletal muscle ECM and their specific roles in the regulation of metabolic diseases. Additionally, we discuss muscle-specific integrins and their role in the regulation of insulin sensitivity. A better understanding of the importance of skeletal muscle ECM remodeling, integrin signaling, and other factors that regulate insulin activity may help in the development of novel therapeutics for managing diabetes and other metabolic disorders.

The Development of Cancer Cachexia Negatively Impacts Skeletal Muscle Extracellular Matrix Remodeling

The Development of Cancer Cachexia Negatively Impacts Skeletal Muscle Extracellular Matrix Remodeling

Multifaceted Interweaving Between Extracellular Matrix, Insulin Resistance, and Skeletal Muscle.

The skeletal muscle provides movement and support to the skeleton, controls body temperature, and regulates the glucose level within the body. This is the core tissue of insulin-mediated glucose uptake via glucose transporter type 4 (GLUT4). The extracellular matrix (ECM) provides integrity and biochemical signals and plays an important role in myogenesis. In addition, it undergoes remodeling upon injury and/or repair, which is also related to insulin resistance (IR), a major cause of type 2 diabetes (T2DM). Altered signaling of integrin and ECM remodeling in diet-induced obesity is associated with IR. This review highlights the interweaving relationship between the ECM, IR, and skeletal muscle. In addition, the importance of the ECM in muscle integrity as well as cellular functions is explored. IR and skeletal muscle ECM remodeling has been discussed in clinical and nonclinical aspects. Furthermore, this review considers the role of ECM glycation and its effects on skeletal muscle homeostasis, concentrating on advanced glycation end products (AGEs) as an important risk factor for the development of IR. Understanding this complex interplay between the ECM, muscle, and IR may improve knowledge and help develop new ideas for novel therapeutics for several IR-associated myopathies and diabetes.

Meta-fibrosis links positive energy balance and mitochondrial metabolism to insulin resistance.

Obesity and insulin resistance often emerge from positive energy balance and generally are linked to low-grade inflammation. This low-grade inflammation has been called “meta-inflammation” because it is a consequence of the metabolic dysregulation that can accompany overnutrition. One means by which meta-inflammation is linked to insulin resistance is extracellular matrix expansion secondary to meta-inflammation, which we define here as “meta-fibrosis”. The significance of meta-fibrosis is that it reflects a situation in which the extracellular matrix functions as a multi-level integrator of local (for example, mitochondrial reactive oxygen species production) and systemic (for example, inflammation) inputs that couple to cellular processes creating insulin resistance. While adipose tissue extracellular matrix remodeling has received considerable attention, it is becoming increasingly apparent that liver and skeletal muscle extracellular matrix remodeling also contributes to insulin resistance. In this review, we address recent advances in our understanding of energy balance, mitochondrial energetics, meta-inflammation, and meta-fibrosis in the development of insulin resistance.

Changes in microvascular density differentiate metabolic health outcomes in monkeys with prior radiation exposure and subsequent skeletal muscle ECM remodeling.

Radiation exposure accelerates the onset of age-related diseases such as diabetes, cardiovascular disease, and neoplasia and, thus, lends insight into in vivo mechanisms common to these disorders. Fibrosis and extracellular matrix (ECM) remodeling, which occur with aging and overnutrition and following irradiation, are risk factors for development of type 2 diabetes mellitus. We previously demonstrated an increased incidence of skeletal muscle insulin resistance and type 2 diabetes mellitus in monkeys that had been exposed to whole body irradiation 5-9 yr prior. We hypothesized that irradiation-induced fibrosis alters muscle architecture, predisposing irradiated animals to insulin resistance and overt diabetes. Rhesus macaques (Macaca mulatta, n = 7-8/group) grouped as nonirradiated age-matched controls (Non-Rad-CTL), irradiated nondiabetic monkeys (Rad-CTL), and irradiated monkeys that subsequently developed diabetes (Rad-DM) were compared. Prior radiation exposure resulted in persistent skeletal muscle ECM changes, including a relative overabundance of collagen IV and a trend toward increased transforming growth factor-β1. Preservation of microvascular markers differentiated the irradiated diabetic and nondiabetic groups. Microvascular density and plasma nitrate and heat shock protein 90 levels were lower in Rad-DM than Rad-CTL. These results are consistent with a protective effect of abundant microvasculature in maintaining glycemic control within radiation-induced fibrotic muscle.

Skeletal muscle extracellular matrix remodeling after short-term overfeeding in healthy humans

BackgroundSkeletal muscle extracellular matrix (ECM) remodeling has been proposed as a feature of the pathogenic milieu associated with obesity and metabolic dysfunction. The aim of the current study was to examine the timeline of this response and determine whether 3 and 28days of overfeeding alters markers of ECM turnover. MethodsForty healthy individuals were overfed by 1250kcal/day for 28days. Hyperinsulinemic–euglycemic clamps and abdominal fat distribution were performed at baseline and day 28 of overfeeding and skeletal muscle biopsies taken at baseline, day 3 and day 28. mRNA expression (COL1a1, COL3a1, MMP2, MMP9, TIMP1, CD68, Integrin) was performed in 19 subjects that consented to having all biopsies performed and microarray analysis was performed in 8 participants at baseline and day 28. ResultsIn the whole cohort, body weight increased by 0.6±0.1 and 2.7±0.3kg at days 3 and 28 (both P<0.001), respectively. Glucose infusion rate during the hyperinsulinemic–euglycemic clamp decreased from 54.8±2.8 at baseline to 50.3±2.5μmol/min/kg FFM at day 28 of overfeeding (P=0.03). Muscle COL1 and COL3 and MMP2 mRNA levels were significantly higher 28days after overfeeding (all P<0.05), with no significant changes in MMP9, TIMP1, CD68 and integrin expression. Microarray based gene set tests revealed that pathways related to ECM receptor interaction, focal adhesion and adherens junction were differentially altered. ConclusionsSkeletal muscle ECM remodeling occurs early in response to over-nutrition with as little as 3% body weight gain. Our findings contribute to the growing evidence linking muscle ECM remodeling and accumulation as another sequela of obesity-related insulin resistance.

Weight Gain Reveals Dramatic Increases in Skeletal Muscle Extracellular Matrix Remodeling

In animal models of obesity, chronic inflammation and dysregulated extracellular matrix remodeling in adipose tissue leads to insulin resistance. Whether similar pathophysiology occurs in humans is not clear. The aim of this study was to test whether 10% weight gain induced by overfeeding triggers inflammation and extracellular matrix remodeling (gene expression, protein, histology) in skeletal muscle and sc adipose tissue in humans. We also investigated whether such remodeling was associated with an impaired metabolic response (hyperinsulinemic-euglycemic clamp). Twenty-nine free-living males were fed 40% over their baseline energy requirements for 8 weeks. Ten percent body weight gain prompted dramatic up-regulation of a repertoire of extracellular matrix remodeling genes in muscle and to a lesser degree in adipose tissue. The amount of extracellular matrix genes in the muscle were directly associated with the amount of lean tissue deposited during overfeeding. Despite weight gain and impaired insulin sensitivity, there was no change in local adipose tissue or systemic inflammation, but there was a slight increase in skeletal muscle inflammation. We propose that skeletal muscle extracellular matrix remodeling is another feature of the pathogenic milieu associated with energy excess and obesity, which, if disrupted, may contribute to the development of metabolic dysfunction.