Abstract
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.
Introduction
Skeletal muscle is a tissue mainly composed of muscle fibers, which form multinucleated contractile cells. It accounts for approximately 30% of women's body weight and 40% of men's body weight and is essential for locomotion, protection, and support of the skeleton. It also plays a critical role in physiological processes, namely in regulating body temperature, maintaining glucose homeostasis in the body, and maintaining continuity of communication with other tissues through the secretion of many peptides (1). Skeletal muscle is the main metabolic tissue that uptakes about 85% of glucose in response to insulin stimulation via the glucose transporter type 4 (GLUT4). Therefore, disorders associated with lower sensitivity of skeletal muscle to insulin, defined as insulin resistance (IR), contribute to the development of obesity, type 2 diabetes mellitus (T2DM), and cardiovascular diseases. Skeletal muscle insulin action is decreased in prediabetes and T2DM, but it also may be largely variable even among healthy individuals with normal glucose tolerance. The phenotype of insulin function is influenced by many familial, genetic, and environmental factors of a particular individual. Lifestyle factors, i.e. physical activity and diet, are also of great importance (2).
Insulin interacts with receptors in the cell membrane. It thus stimulates signal transduction pathway. Insulin signaling molecules include insulin receptor substrate 1 (IRS1), phosphatidylinositol 3-kinase (PI3K), and protein kinase B, known also as Akt. Transduction of insulin signal leads to a cascade of protein phosphorylation and to GLUT4 glucose transporter translocation from the cytoplasm to the plasma membrane and to the stimulation of cellular glucose uptake (Fig. 1) (3). The reduced activity of insulin is due to the reduced potential of insulin to stimulate the functioning of various factors of the insulin signaling system, such as tyrosine phosphorylation of the insulin receptor and IRS1 and downstream signaling molecules (4, 5). Multiple pathological mechanisms can impair insulin action, including increased fatty acid metabolites, inflammation, and mitochondrial dysfunction (6). What is important, IR is also related to the extracellular matrix (ECM) that surrounds muscle fibers and is made of many components, including collagen and a mixture of other macromolecules: glycoproteins and proteoglycans. It performs many essential functions, including the development, growth, and repair of muscles and the transmission of contraction force. Therefore, the correct operation of the ECM and the muscle fibers that make up the skeletal muscle is crucial for the proper functioning of the body (1).
Mechanism of glucose uptake by insulin stimulation. Insulin binds to the insulin receptor (IRS1) and activates tyrosine phosphorylation and then protein kinase B (AKT). Glucose transporter type 4 (GLUT4) is translocated from the intracellular space to the cell membrane. GLUT4 integrates into the cell membrane and activates glucose uptake.
Citation: Endocrine Connections 12, 5; 10.1530/EC-23-0023
The aim of this article is to describe ECM remodeling in skeletal muscle and its contribution to the development of metabolic diseases. The review presents a close relationship ,between abnormal ECM remodeling and IR, leading to metabolic disorders.
Structure and functions of the ECM of skeletal muscle
Skeletal muscle ECM structure
The ECM of skeletal muscle is built of a three-dimensional, multi-planar mesh of many proteoglycans and fibrous proteins such as collagens, laminins, elastins, and fibronectins. The most important structural protein of the ECM of skeletal muscle is collagen, which is present at the level of 1–10% of dry muscle mass (7). The ECM is divided into two types: interstitial and pericellular matrices. The first type is the connective tissue matrix, which includes a mixture of collagens, proteoglycans, elastins, fibronectin, and glycosaminoglycans. The pericellular matrices interact with cells and have a more diverse molecular composition compared to the interstitial matrix (8). In the ECM of skeletal muscle, three separate and interrelated integuments are distinguished, namely epimysium, perimysium, and endomysium. The epimysium is a dense connective tissue that is the outermost layer and surrounds the entire muscle. It is made of many components, including type I collagen, fibronectin, undulin, and tenascin. The perimysium is the middle layer derived from the epimysium that wraps the muscle bundles, otherwise known as the muscle fasciculus. It consists mainly of various types of collagen (I, III, V, and VI), fibronectin, dermatan sulfate, and decorin. The third innermost layer enveloping a single muscle fiber is the endomysium, otherwise known as the basal lamina or membrane. This layer is the most refined structure and consists mainly of collagen type IV, fibronectin, laminin, nidogen, and many other ingredients (Fig. 2) (9, 10). The endomysium contains an inner layer whose components interact with the elements of the sarcolemma and an outer mesh layer (9). Thanks to the coherence of all components of this coating, damaged muscle fibers are regenerated. Basal membrane disorders may lead to the formation of band dystrophy of the limbs (limb-girdle muscular dystrophy; LGMD). Components such as collagen type IV, laminin, and nidogen present in the myogenic area of the limb germ are involved in the formation of endomysium (11). In turn, proteins such as the dystrophin–glycoprotein complex (DGC), vinculin, and perlecan occur between the sarcolemma and the endomysium and are connected by microfilaments (9). Also, a very important protein in the ECM is merosine, also known as laminin-211 because it binds to the sarcolemma and to the collagen, which is part of the endomysium, creating a mechanical connection between them. In addition, its deficiency contributes to the disorder of muscle contraction as well as the transfer of force (12). The next important receptor is the plasminogen activator inhibitor-1, which binds the ECM to the cell surface and thus enables the formation of multimolecular compounds, for example, it binds to the integrin A5B3 in muscle cells (13). What is more, the basement membrane contains various growth factors, thanks to which it directly participates in the physiological tasks of myocytes, and is also important in the proper maintenance of the physiological functions of skeletal muscle (9).
Structure of the three-layer extracellular matrix of muscles.
Citation: Endocrine Connections 12, 5; 10.1530/EC-23-0023
The ECM contains also receptors and regulators (they are proteins and enzymes that control the cell cycle – they are involved in the physiological and pathological processes of components ECM remodeling and their degradation), for example, integrins and matrix metalloproteinases (MMPs) (9). All components of the ECM (Fig. 3) have different roles and are necessary for the proper maintenance of the physiological functions of skeletal muscle (Table 1).
The relationship between insulin resistance and ECM remodelingAbbreviation: MMP, matrix metalloproteinase; F4/80, macrophage marker; TNFα, marker tumornecrosis factor alpha; COL Iα1, collagen type I alpha I; COL Iα2, collagen type I alpha II; COL IIIα1,collagen type III alpha I; COL IVα1, collagen type IV alpha I; FAK, focal adhesion kinase.
Citation: Endocrine Connections 12, 5; 10.1530/EC-23-0023
Main components of the extracellular matrix (ECM) and their functions.
| ECM | Function | Source |
|---|---|---|
| Collagen | Provides the structural integrity of the tissue, resistance to stretching and muscle stiffness, control of processes such as adhesion, migration, cell differentiation, and participation in interaction with membrane receptors | (14, 16) |
| Laminin | Supports processes such as proliferation, differentiation, and cell adhesion, ensures structural integrity of the ECM basement membrane, protects against injuries, takes part in muscle regeneration, and inhibits inflammation | (9, 14, 20, 21) |
| Fibronectin | Supports processes such as proliferation, differentiation, and cell adhesion, initiates the movement of nuclei in muscle fibers to their periphery, and ensures participation in interaction with membrane receptors | (9, 24) |
| Elastin | Supports processes such as proliferation, differentiation, and cell adhesion, and is responsible for the flexibility and elasticity of the muscles | (9) |
| Proteoglycan, e.g. perlecan and decorin | Participates in connecting the internal cytoskeleton and ECM | (9) |
| Glycosaminoglycan, e.g. hyaluronan and dermatan sulfate | Supports processes such as proliferation and differentiation cell | (9) |
| Dystrophin | Responsible for proper communication between the cytoskeleton and the ECM of skeletal muscle while maintaining the integrity of the cell membrane and ensures the proper formation of a stable attachment of muscle fibers during the development of skeletal muscles | (9) |
| Dystroglycan | Is responsible for proper communication between the cytoskeleton and the ECM of skeletal muscle while maintaining the integrity of the cell membrane and maintains the stability of myotubes | (9) |
| Integrin | Is responsible for proper communication between the ECM of skeletal muscle and inside the cell and participates in the physiological processes of cells such as adhesion, movement, survival, differentiation, reproduction, and cell death | (29, 30) |
| Matrix metalloproteinase | Supports the control of the cell cycle and participates in the physiological and pathological processes of remodeling ECM components and their degradation | (9) |
Collagen
A key component of the ECM is collagens, which are the most abundant proteins in mammals. They are classified into a family of 46 genes encoding 28 different types of proteins. All types of collagen proteins are made of polypeptide chains that contain homotrimers and heterotrimers. Among the 28 classified forms of collagen, 11 of them occur in mature skeletal muscle, and they are the following types: I, III, IV, V, VI, XII, XIII, XIV, XV, XVIII, and XXII (14). The most abundant collagens found in skeletal muscle are collagen fibers classified as type I and III, which are present at the level of 75% of the total amount of this protein in muscle tissue (15). In the ECM of skeletal muscle, collagens play an important role in controlling cell adhesion and differentiation, thus enabling bones to be flexible as well as resist stretching (14). Collagen I is present in all ECM layers of the skeletal muscle forming parallel fibers, and its role is to generate tensile strength as well as stiffness in the skeletal muscle. On the other hand, collagen III (collagen III A1 chain –- COL3A1) occurs in the basal lamina and perimysium, forming a thin network of fibers (16). The basic component that builds the endomysium is collagen type IV, which is secreted by myogenic and fibrogenic cells, thanks to which it is one of the factors enabling the movement, differentiation, and connection of myoblasts, making the regeneration of skeletal muscle possible (14, 17). As a result of the COL4A1 gene mutation, the secretion of the COL4A1, A2, and A3 trimers may be disturbed, which leads to abnormalities, such as basement membrane damage, local inflammatory infiltration, central nuclei concentration, as well as improper deposition of the ECM, which is ultimately associated with muscle fiber atrophy (18, 19). Collagen VI plays an important role in maintaining the proper physiological function of muscle tissue, partly through reaction with other components of the ECM and cell surface receptors (9, 14). Deficiency of this type of protein can contribute to the damage of ECM components, which in turn leads to abnormal functioning of muscles, proteins, organelles (mitochondria), as well as esterification of microtubule proteins, which is associated with faster aging and myopathy (9).
Laminin
Laminin belongs to heterotrimeric glycoproteins and is found mainly in the endomysium, thanks to which it supports processes such as proliferation, differentiation, and cell adhesion. Its deficit causes disorders in the construction of the ECM, which affects the physiological function of skeletal muscle (20). There are many types of laminins, and the most important in the skeletal muscle ECM are laminin-1, laminin-111, and laminin-211 (9).
Laminin-1 supports the maintenance of integrity between muscle fibers and the basement membrane of the ECM, inhibits inflammation of skeletal muscle, accelerates regenerative processes, and supports the proliferation and movement of myoblasts (9). Laminin-111 affects the stimulation of the expression of integrin 7, stabilizes the composition of the basement membrane, and provides protection of the skeletal muscle against injuries (21). Laminin-211 is the most common isoform of these glycoproteins in the ECM of mature skeletal muscle. It is made up of three chains: alpha2, beta1, and gamma 1. The biological role of laminins depends on their attachment to cell surface receptors, which include two groups: integrins and non-integrins. The primary receptor for this glycoprotein in skeletal muscle is the integrin alpha 7 beta 1, and the non-integrin receptor is dystroglycan, which is complex with dystrophin (DGC) (22, 23). Other less common non-integrin receptors that bind to laminin-211 include syndecans and sulfatides (14). Laminine-211 also interacts with other components of the skeletal muscle ECM, namely nidogen, perlecan, and agrin (20).
Fibronectin
Fibronectin is found in three layers of the ECM of the skeletal muscle. It binds to tenascin-C at the tendon junction (10). This protein is produced by fibroblasts and also activates integrin proteins via the FAK/Scr pathway and thus initiates the movement of nuclei in muscle fibers to their periphery (24). Furthermore, fibronectin and collagen can be upregulated by the transforming growth factor β (TGF-β) and thus may accumulate in the ECM leading to tissue fibrosis (25). This protein can also promote myoblast attachment and differentiation as well as limit its migration and division (9). Fibronectin also supports the connection and linear arrangement of myoblast tubes during their differentiation (26). A deficiency of this protein may contribute to disorders in the construction of the ECM, as well as muscle tubules, resulting in improper functioning of skeletal muscle (9).
Hyaluronan
Hyaluronan is a linear polysaccharide composed of a disaccharide repeating unit containing glucuronic acid and N-acetylglucosamine. It is an important component of the ECM because it creates free spaces between cells and activates signaling pathways related to cell adhesion, proliferation, migration, and differentiation (27).
Integrin
Integrins are signaling receptors belonging to the family of glycoproteins, which are composed of two independent subunits connected by a non-covalent bond. All of these proteins have subunits containing large extracellular domains that are involved in ligand binding, transmembrane domains, and smaller cytoplasmic tails that are approximately 20–70 amino acids long. In skeletal muscle, 7A subunits (A1, A3, A4, A5, A6, A7, and AV) have been detected in association with the B1 subunit (28, 29). In higher organisms, 24 integrins are currently known, resulting from the combination of 18A subunits and 8B subunits, thanks to which they have different ligand-binding properties. Integrins enable two-way signaling (meaning ‘inside-out’ and ‘outside-in’ signaling) (29, 30). Thanks to this signaling, proteins (for example α-actinins, filamins, talins, and vinculins) are synthesized, which bind actin and adapter proteins (more than 40) and connect with the help of integrins to the actin cytoskeleton (31). These receptors are of great importance in the physiological processes of cells because they affect their adhesion, movement, survival, differentiation, reproduction, and cell death (30). Integrins bind to ECM components such as collagen (A1B1 and A2B1), fibronectin (A4B1, A5B1, and AVB3), laminin (A3B1 and A6B1), and vitronectin (AVB3, AVB5) (32). In addition, integrins act as a hub for signaling pathways such as PI3Ks and mitogen-activated protein kinases, which are essential to maintain normal cellular properties (28). They can also stimulate Ras family GTPases, Rho, which play an important role in the organization and dynamics of the cytoskeleton (31).
Dystrophin complex
Dystrophin has an N-terminal protein that binds to actin via an actin-binding domain (ABD), and each domain has two calmodulin proteins (9). Interestingly, three mutations in an ABD domain of dystrophin in the skeletal muscle in Duchenne disease have been found and, as a consequence, there is an impediment to the junction of dystrophin with actin, causing damage to the bonds between the myocyte membrane and the skeletal muscle ECM (33). Dystroglycan is a transmembrane protein with two A and B subunits (14). It is located on the outer surface of the basal lamina of muscle fibers and thus participates in the connection of endomysium with myocytes (9). Thanks to the connection with laminin-211, it maintains the stability of the myotube during the contraction of the muscle tissue (34). Both of these compounds form a DGC together with other proteins such as utrophin or dystrobrevin, and the receptor thus formed is necessary for the ECM components of skeletal muscle for its proper functioning. The DGC is a transmembrane complex composed of both peripheral and integral membrane proteins/glycoproteins, with specific cytoplasmic as well as extracellular protein components also associated with it. The basic component of DGC is dystrophin, which ensures the proper formation of a stable attachment of muscle fibers during the development of skeletal muscles. The DGC complex is bound to the laminin receptor G protein in the ECM of skeletal muscle. It connects the cytoskeletal actins to the ECM of the skeletal muscle and ensures the stability of the neuromuscular synapse. An abnormal peptide chain as well as disturbances in glycosylation and laminin-binding activity leads to the development of muscular dystrophy. The DGC is involved in lateral force transmission between muscle fibers. Disturbance of its structure and function will destroy the lateral transmission, leading to power instability and increasing the sensitivity of muscle fibers to contraction damage (9). In addition, this complex is a platform to which ligands attach, for example, nitric oxide synthase that stimulates glucose transport, so disorders of this receptor contribute to the improper functioning of insulin in the skeletal muscle fibers (35). Both these proteins play a significant role as components necessary for proper communication between the cytoskeleton and the ECM of skeletal muscle while maintaining the integrity of the cell membrane (9).
Skeletal muscle ECM functions
The ECM provides a scaffold for the cell–matrix interaction that is central to many physiological functions in the skeletal muscle. Thanks to this structure, which guarantees a stable microenvironment, it supports processes such as adhesion, movement, division, and differentiation of cells (14). The supporting and regulatory function of the ECM is mandatory for the formation of muscle tubes, which are formed in the early stages of myogenic differentiation (36). Interestingly, ECM remodeling is an important step in the development satellite cell cycle (it affects activation, proliferation, and self-renewal) (37). Myogenic/regenerative potential of skeletal muscle may be an important determinant of insulin sensitivity (6). Intact ECM is involved in the regeneration of muscle fibers in the injured skeletal muscle (14). In a state of skeletal muscle injury or myopathy, the ECM is remodeled because genes such as extracellular matrix protein 1, spondin 1, and thrombospondin 1 are upregulated (38). What is more, the ECM secretes cytokines which activate the proliferation of myogenic progenitor cells and the regeneration of muscle fibers by inducing transcription in these cells (39). Another essential role of ECM components (such as collagen, dystrophin, and integrins) is to participate in the development of the neuromuscular junction, as ECM proteins activate acetylcholinesterase action and regulate synaptogenesis during synaptic induction (40). Therefore, the proper functioning of this connection and the emission of synaptic signals are the basis for ensuring the proper motility of skeletal muscle (41). The next important role of the ECM is to participate in the transmission of force in the skeletal muscle because when the bonding between the ECM and muscle cells is inadequate, the force transmission pathway is destroyed and, consequently, the muscle fibers are deformed (42).
Skeletal muscle and the ECM in association with IR
A rearrangement in the composition of ECM is a characteristic feature of all insulin-resistant muscles. Abnormal ECM remodeling may impair insulin action. Several hypotheses regarding the mechanism of ECM remodeling due to progressive IR have been established (Fig. 4). One of them is the occurrence of microcirculation disorders, which in turn leads to the transfer of smaller amounts of nutrients and hormones to skeletal muscles (2). Another one is the hypothesis suggesting that individual components of the remodeled ECM act to induce IR because the accumulation of collagen, laminin, and fibronectin in the interstitial space leads to the formation of a physical barrier of the ECM and thus increases the diffusion distance for nutrients and hormones to the muscle. In addition, the mechanical linkage between the matrix and IR is indicated to be mediated by integrin signaling via integrin-linked kinase (ILK) and focal adhesion kinase (FAK), both of which are crucial in regulating insulin action (Fig. 5). FAK plays a key role in transmitting the signal from integrins to the inside of the cell (to intracellular protein cascade) and indirectly participates in many cell processes, for example, adhesion, migration, cytoskeleton protein phosphorylation, and apoptosis (29).
Mechanism of abnormal glucose uptake via insulin action and integrin signaling. Development of insulin resistance (IR) as a result of impaired activation of the PI3K, AKT pathways, and GLUT4 trafficking.
Citation: Endocrine Connections 12, 5; 10.1530/EC-23-0023
In turn, IR-associated conditions may further aggravate disturbances of ECM in the skeletal muscle. For example, the excessive quantity of components like collagen, laminin, and fibronectin may be a result of hyperglycemia and is characteristic for T2DM (2, 43). In primates, glucose tolerance was found to deteriorate, worsening glycemic control, mainly resulting in further disturbances of ECM remodeling (44).
The reports are limited, but there is a growing evidence that there is a strong relationship between ECM rearrangement and IR (2).
Remodeling of the ECM as one of the factors of skeletal muscle dysfunction leading to metabolic diseases
Animal studies
ECM remodeling has been observed in rodent studies and is influenced by diet and intracellular signal transduction activity. The HFD (high-fat diet) contributes to inflammation and increases TGF-β signaling, resulting in ECM rearrangement. It was indicated that as a result of the formation of oxidative stress and inflammation, growth factors are stimulated, which include, for example, TGF-β1, and these are involved in the abnormal remodeling of the ECM (45). Studies have shown that HFD mice have elevated levels of pro-inflammatory CD11c+ macrophages in the muscle. Kang and colleagues further confirmed the link between inflammation and abnormal ECM remodeling. In the experiment, they used mice on a 20-week HFD, and the effect was an increase in the content of collagen in the muscles, which was associated with increased expression of genes such as the macrophage marker F4/80 and the pro-inflammatory marker tumor necrosis factor. Furthermore, gene expression of these markers and collagen deposition was lower in the analyzed tissues of mice used as control (normal fed), suggesting that in obese skeletal muscle, the abnormal ECM remodeling is strongly dependent on the formation of inflammatory foci. This experiment proved that in insulin-resistant mice, there is decreased activity of MMP9, and this contributes to some extent to the increased accumulation of collagen. Another study by Kang and colleagues also confirmed this correlation, because, in HFD mice, deletion of MMP9 caused more collagen to be deposited in the muscles, which increased the IR (46, 47). The next experiment examined the level of hyaluronan during HFD feeding in mice. The assays carried out on insulin-resistant animals confirm that there is an increased level of this glycosaminoglycan in the skeletal muscle in vivo and aorta in vitro (48, 49). In addition, in the research using the hyperinsulinemic–euglycemic clamp, it has been proven that the reduction in the level of hyaluronan in muscles as a result of intravenous administration of pegylated human recombinant hyaluronidase PH-20 (PEGPH20) causes higher glucose infusion rate and uptake by muscles, which is related to the administered PH-20 dose. Thanks to this effect, reducing the content of this polysaccharide in HFD mice increases insulin sensitivity (48). In further studies, this team proved that insulin-resistant mice with MMP9 deletion have reduced muscle capillaries. These observations strongly influence abnormal ECM remodeling as less capillarity creates greater spatial barriers and impedes the diffusion of hormones and nutrients. Moreover, Kang and colleagues confirmed that in HFD mice, the improvement in muscle insulin function was accompanied by an increase in muscle capillaries. These observations were found in several applied study models, namely, in the first of them, rodents were treated with hyaluronidase and in the next, they were treated with sildenafil, and in the third, they were transgenic organisms with mitochondrial catalase (46, 47, 48).
Subsequent experiments examined the activity of membrane receptors such as CD44 and integrins, which play a significant role in the regulation of insulin action (14). Less studies have been performed on the effects of signaling receptors (for instance, integrins) in the skeletal muscle in the context of assessing insulin sensitivity in vivo conditions. Zong and colleagues conducted analyses that show that in the muscles of mice with a deletion of the integrin B1 subunit raised using a normal diet (chow fed), there is a decrease in glucose uptake in muscles stimulated with insulin during the hyperinsulinemic–euglycemic clamp. Interestingly, deletion of the integrin A2 subunit in the muscle of the HFD mice somewhat reverses the resulting IR, as demonstrated by an increased insulin signaling and glucose uptake during the clamp. The results of the studies suggest that there is a strong relationship among the signaling of integrins, which are the mechanistic link between the muscle ECM and the IR as A2 and B1 integrins interact with collagen but activate other signaling pathways (46). Moreover, FAK is a tyrosine kinase with intracellular signaling properties regulated by insulin receptors. In muscle, it regulates glucose uptake by GLUT4 translocation via actin remodeling. FAK overexpression results in actin reorganization and subsequent glucose uptake under IR conditions. In contrast, under the same conditions, FAK silencing decreases actin remodeling, which is associated with reduced GLUT4 translocation and glucose uptake, resulting in the deepening of the IR. Therefore, FAK is also related to HFD (29). This is confirmed in a few reports for animals. Bisht and colleagues showed that in the muscles of HFD rats, there is a reduced level of tyrosine phosphorylation of FAK. The knockdown of FAK with siRNA-mediated in vivo results in impaired glucose uptake and reduced insulin action in HFD mice. In addition, overexpression of FAK in C2C12 cell lines increased glucose tolerance, and transfecting these cells with siRNA to silence FAK had the opposite effect. Experiments performed on rat cell lines (L6) give similar results, i.e. lower glucose uptake due to weaker insulin signaling, as well as reduced glycogen synthesis and impaired GLUT4 translocation after FAK silencing (50, 51, 52, 53). Interestingly, ILK shares the adapter protein Nck2 with the insulin receptor, which suggests that it may affect the physical relationship between the insulin receptor and integrins. Their communication disorders may lead to the development of IR, but there is too little data on this topic (29). Based on the analyses carried out, it was only found that mice with an ILK deletion in the muscles have the possibility of continuing life (26).
Given the information presented, abnormal ECM remodeling is a hallmark of IR that occurs in obese rodents, and these are at greater risk of developing metabolic diseases. An abnormal ECM remodeling is influenced by many factors that are closely related, including, for example, diet, inflammation, impaired glucose metabolism, and signal transduction activity (30).
Clinical studies
Based on several clinical studies, it was found that there is a relationship between abnormal ECM remodeling and IR, and it occurs in obese individuals and in individuals with metabolic disorders such as hyperglycemia, hyperinsulinemia, and dyslipidemia. Richardson and colleagues showed an increase in ECM gene expression and collagen accumulation in the skeletal muscle of healthy individuals due to the rise in plasma free fatty acid concentrations, which induces IR (54). A subsequent study by Berria and colleagues confirmed that abnormal ECM remodeling occurs in the IR skeletal muscle in obese nondiabetic subjects and patients with well-controlled T2DM where collagen levels (mainly types I and III) increase (55). The following results by Watts and colleagues show that the change in ECM composition in less insulin-sensitive muscles in morbidly obese subjects is affected by increased TGF-β signaling (56). In addition, another study showed that in obese people, there was an increase in the concentration of a potent anti-anabolic muscle mass regulator myostatin in myotubes and plasma, and this component was positively correlated with IR (57). Upregulation of ECM genes (SPARC, integrin, and collagens I, III, IV, and V) is caused by skeletal muscle inflammation resulting from HFD. Interestingly, this experiment found that adipose tissue showed negligible changes in abnormal ECM remodeling, and it did not demonstrate inflammation despite detecting IR (58). Later studies performed by the same research team also showed a strong association between ECM composition changes and decreased insulin sensitivity due to weight gain through HFD. The obtained results demonstrated an increase in the expression of ECM genes such as collagen I and III and MMP2, which participate in interactions with ECM receptors, including focal adhesion and adheren junctions (59). Recent studies show that the c rs4607103 ADAM metallopeptidase allele is associated with reduced insulin sensitivity and increased levels of ADAMTS9 expression in the human skeletal muscle (60).
It has been proven that physical exercise has a positive effect on the improvement of insulin sensitivity in muscles because there is an increase in the mechanical load in this tissue, which stimulates and activates proteases (MMPs) and enables the normal remodeling of the ECM (1). Physical activity has been shown to increase the expression of the MMP2, MMP9, and ADAMTS1 genes in human skeletal muscle cells (14). It is suggested that the contradictory results of MMP2 and ADAMTS presented above regarding insulin sensitivity depend on the proper/abnormal remodeling of the ECM of the skeletal muscle and its physical state (obese, lean, damaged, and diseased). These genes are upregulated to maintain homeostasis of muscle fiber integrity by degrading ECM proteins or promoting migration, proliferation, and differentiation in injured and diseased muscles. In addition, resistance exercise can upregulate an inhibitor of metalloproteinases, for example, tissue inhibitor of metalloproteinases 2 – a gene and a corresponding protein that is involved in ECM degradation, so that the IR is reduced (1, 14). Interestingly, there are genes whose regulation by exercise is age dependent. These include also MMP9 and MMP15, as it was shown that the first of them had an increased expression in young people, while in the elderly, a reduced expression of MMP9 and MMP15 was found (14).
Accordingly, abnormal ECM remodeling is known to be influenced by many factors that create a vicious cycle (namely, poor diet, impaired signaling transduction, impaired glucose homeostasis, and inflammation), leading to obesity and metabolic disorders. Therefore, abnormal ECM remodeling is believed to be a hallmark of metabolic diseases such as T2DM.
Concluding remarks and future perspectives
In recent years, it has been suggested that changes in ECM components cause abnormalities in insulin signaling and action. Therefore, studies were conducted in which it was observed that there was a positive correlation between ECM rearrangement and human and animal skeletal muscle IR with obesity and T2DM. Additionally, it was found that disorders in this structure were also associated with the formation of inflammation. With this information, modifications in the skeletal muscle ECM composition were identified as a mechanism of IR, which attracted the attention of many researchers and clinicians. However, there are still many unknowns, such as how ECM reorganization regulates insulin function. There are two main hypotheses, the first of which proposes that during the development of obesity, there is an abnormal remodeling of the ECM, which composes a mechanical barrier and thus hinders the transport of insulin and glucose in the muscles. The second of them indicates that disorders in the structure of the ECM cause impairments in the communication of signaling pathways of receptors, such as integrins, which directly may inhibit insulin signaling and play a significant role in the proper functioning of insulin. Therefore, further studies should be performed on the relationship between changes in the ECM composition of insulin-resistant skeletal muscle and the relationship between insulin action and receptor signaling (mainly integrins), which will possibly enable the development of new therapeutics used in the treatment of IR-associated metabolic diseases.
Declaration of interest
The authors declare no conflict of interest
Funding
This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
References
- 1↑
Csapo R, Gumpenberger M, & Wessner B. Skeletal muscle extracellular matrix – what do we know about its composition, regulation, and physiological roles? A narrative review. Frontiers in Physiology 2020 11 253. (https://doi.org/10.3389/fphys.2020.00253)
- 2↑
Ahmad K, Lee EJ, Moon JS, Park SY, & Choi I. Multifaceted interweaving between extracellular matrix, insulin resistance, and skeletal muscle. Cells 2018 7 148. (https://doi.org/10.3390/cells7100148)
- 3↑
Turcotte LP, & Fisher JS. Skeletal muscle insulin resistance: roles of fatty acid metabolism and exercise. Physical Therapy 2008 88 1279–1296. (https://doi.org/10.2522/ptj.20080018)
- 4↑
Krook A, Björnholm M, Galuska D, Jiang XJ, Fahlman R, Myers MG Jr, Wallberg-Henriksson H, & Zierath JR. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 2000 49 284–292. (https://doi.org/10.2337/diabetes.49.2.284)
- 5↑
Colleta DK, & Mandarino LJ. Mitochondrial dysfunction and insulin resistance from the outside in: Extracellular matrix, the cytoskeleton, and mitochondria. American Journal of Physiology. Endocrinology and Metabolism 2011 301 E749–E755. (https://doi.org/10.1152/ajpendo.00363.2011)
- 6↑
Stefanowicz M, Nikolajuk A, Matulewicz N, Strączkowski M, & Karczewska-Kupczewska M. Skeletal muscle RUNX1 is related to insulin sensitivity through its effect on myogenic potential. European Journal of Endocrinology 2022 187 143–157. (https://doi.org/10.1530/EJE-21-0776)
- 7↑
Gillies AR, & Lieber RL. Structure and function of the skeletal muscle extracellular matrix. Muscle and Nerve 2011 44 318–331. (https://doi.org/10.1002/mus.22094)
- 8↑
Ahmad K, Shaikh S, Ahmad SS, Lee EJ, & Choi I. Cross-talk between extracellular matrix and skeletal muscle: implications for myopathies. Frontiers in Pharmacology 2020 11 142. (https://doi.org/10.3389/fphar.2020.00142)
- 9↑
Zhang W, Liu Y, & Zhang H. Extracellular matrix: an important regulator of cell functions and skeletal muscle development. Cell and Bioscience 2021 11 65. (https://doi.org/10.1186/s13578-021-00579-4)
- 10↑
Kannus P, Jozsa L, Jarvinen TA, Jarvinen TL, Kvist M, Natri A, & Jarvinen M. Location and distribution of non-collagenous matrix proteins in musculoskeletal tissues of rat. Histochemical Journal 1998 30 799–810. (https://doi.org/10.1023/A:1003448106673)
- 11↑
Li M, Dickson DW, & Spiro AJ. Abnormal expression of laminin beta 1 chain in skeletal muscle of adult-onset limb-girdle muscular dystrophy. Archives of Neurology 1997 54 1457–1461. (https://doi.org/10.1001/archneur.1997.00550240013007)
- 12↑
Jannapureddy SR, Patel ND, Hwang W, & Boriek AM. Genetic models in applied physiology. Merosin defciency leads to alterations in passive and active skeletal muscle mechanics. Journal of Applied Physiology 2003 94 2524–2523. (https://doi.org/10.1152/japplphysiol.01078.2002)
- 13↑
Planus E, Barlovatz-Meimon G, Rogers RA, Bonavaud S, Ingber DE, & Wang N. Binding of urokinase to plasminogen activator inhibitor type-1 mediates cell adhesion and spreading. Journal of Cell Science 1997 110 1091–1098. (https://doi.org/10.1242/jcs.110.9.1091)
- 14↑
Ahmad K, Choi I, & Lee YH. Implications of skeletal muscle extracellular matrix remodeling in metabolic disorders: diabetes perspective. International Journal of Molecular Sciences 2020 21 3845. (https://doi.org/10.3390/ijms21113845)
- 15↑
McKee TJ, Perlman G, Morris M, & Komarova SV. Extracellular matrix composition of connective tissues: a systematic review and meta-analysis. Scientific Reports 2019 9 10542. (https://doi.org/10.1038/s41598-019-46896-0)
- 16↑
Kovanen V. Intramuscular extracellular matrix: complex environment of muscle cells. Exercise and Sport Sciences Reviews 2002 30 20–25. (https://doi.org/10.1097/00003677-200201000-00005)
- 17↑
Ito A, Yamamoto M, Ikeda K, Sato M, Kawabe Y, & Kamihira M. Efects of type IV collagen on myogenic characteristics of IGF-I gene-engineered myoblasts. Journal of Bioscience and Bioengineering 2015 119 596–603. (https://doi.org/10.1016/j.jbiosc.2014.10.008)
- 18↑
Liu C, ,Li L, Ge M, Gu L, Wang M, Zhang K, Su Y, Zhang Y, Liu Ch, Lan M, et al.Overexpression of miR-29 leads to myopathy that resemble pathology of Ullrich congenital muscular dystrophy. Cells 2019 8 459. (https://doi.org/10.3390/cells8050459)
- 19↑
Guiraud S, Migeon T, Ferry A, Chen Z, Ouchelouche S, Verpont MC, Sado Y, Allamand V, Ronco P, Plaisier E, et al.HANAC Col4a1 mutation in mice leads to skeletal muscle alterations due to a primary vascular defect. American Journal of Pathology 2017 187 505–516. (https://doi.org/10.1016/j.ajpath.2016.10.020)
- 20↑
Holmberg J, & Durbeej M. Laminin-211 in skeletal muscle function. Cell Adhesion and Migration 2013 7 111–121. (https://doi.org/10.4161/cam.22618)
- 21↑
Rooney JE, Gurpur PB, & Burkin DJ. Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy. PNAS 2009 106 7991–7996. (https://doi.org/10.1073/pnas.0811599106)
- 22↑
Burkin DJ, & Kaufman SJ. The alpha7beta1 integrin in muscle development and disease. Cell and Tissue Research 1999 296 183–190. (https://doi.org/10.1007/s004410051279)
- 23↑
Ervasti JM, & Campbell KP. Membrane organization of the dystrophin-glycoprotein complex. Cell 1991 66 1121–1131. (https://doi.org/10.1016/0092-8674(9190035-W)
- 24↑
Roman W, Martins JP, & Gomes ER. Local arrangement of fbronectin by myofbroblasts governs peripheral nuclear positioning in muscle cells. Developmental Cell 2018 46 102–111.e6. (https://doi.org/10.1016/j.devcel.2018.05.031)
- 25↑
Arno B, Galli F, Roostalu U, Aldeiri BM, Miyake T, Albertini A, Bragg L, Prehar S, McDermott JC, Cartwright EJ, et al.TNAP limits TGF-beta-dependent cardiac and skeletal muscle fbrosis by inactivating the SMAD2/3 transcription factors. Journal of Cell Science 2019 132 jcs234948. (https://doi.org/10.1242/jcs.234948)
- 26↑
Vaz R, Martins GG, Thorsteinsdóttir S, & Rodrigues G. Fibronectin promotes migration, alignment and fusion in an in vitro myoblast cell model. Cell and Tissue Research 2012 348 569–578. (https://doi.org/10.1007/s00441-012-1364-1)
- 27↑
Amorim S, Reis CA, Reis RL, & Pires RA. Extracellular matrix mimics using hyaluronan-based biomaterials. Trends in Biotechnology 2021 39 90–104. (https://doi.org/10.1016/j.tibtech.2020.06.003)
- 28↑
Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002 110 673–687. (https://doi.org/10.1016/S0092-8674(0200971-6)
- 29↑
Williams AS, Kang L, & Wasserman DH. The extracellular matrix and insulin resistance. Trends in Endocrinology and Metabolism 2015 26 357–366. (https://doi.org/10.1016/j.tem.2015.05.006)
- 30↑
Huang J, Li X, Shi X, Zhu M, Wang J, Huang S, Huang X, Wang H, Li L, Deng H, et al.Platelet integrin αIIbβ3: signal transduction, regulation, and its therapeutic targeting. Journal of Hematology and Oncology 2019 2 1–22. (https://doi.org/10.1186/s13045-019-0709-6)
- 31↑
Pulous FE, & Petrich BG. Integrin-dependent regulation of the endothelial barrier. Tissue Barriers 2019 7 1685844. (https://doi.org/10.1080/21688370.2019.1685844)
- 32↑
Stupack DG, & Cheresh DA. ECM remodeling regulates angiogenesis: endothelial integrins look for new ligands. Science’s STKE: Signal Transduction Knowledge Environment 2002 2002 pe7. (https://doi.org/10.1126/stke.2002.119.pe7)
- 33↑
Norwood FL, Sutherland-Smith AJ, Keep NH, & Kendrick-Jones J. The structure of the N-terminal actin-binding domain of human dystrophin and how mutations in this domain may cause Duchenne or Becker muscular dystrophy. Structure 2000 8 481–491. (https://doi.org/10.1016/s0969-2126(0000132-5)
- 34↑
Gullberg D, & Ekblom P. Extracellular matrix and its receptors during development. International Journal of Developmental Biology 1995 39 845–854.
- 35↑
Paco S, Casserras T, Rodríguez MA, Jou C, Puigdelloses M, Ortez CI, Diaz-Manera J, Gallardo E, Colomer J, Nascimento A, et al.Transcriptome analysis of Ullrich congenital muscular dystrophy fibroblasts reveals a disease extracellular matrix signature and key molecular regulators. PLoS One 2015 10 e0145107. (https://doi.org/10.1371/journal.pone.0145107)
- 36↑
Langen RC, Schols AM, Kelders MC, Wouters EF, & Janssen-Heininger YM. Enhanced myogenic differentiation by extracellular matrix is regulated at the early stages of myogenesis. In Vitro Cellular and Developmental Biology. Animal 2003 39 163–169. (https://doi.org/10.1007/s11626-003-0011-2)
- 37↑
Rayagiri SS, Ranaldi D, Raven A, Mohamad Azhar NIF, Lefebvre O, Zammit PS, & Borycki AG. Basal lamina remodeling at the skeletal muscle stem cell niche mediates stem cell self-renewal. Nature Communications 2018 9 1075. (https://doi.org/10.1038/s41467-018-03425-3)
- 38↑
Marotta M, Ruiz-Roig C, Sarria Y, Peiro JL, Nunez F, Ceron J, Munell F, & Roig-Quilis M. Muscle genome-wide expression profiling during disease evolution in mdx mice. Physiological Genomics 2009 37 119–132. (https://doi.org/10.1152/physiolgenomics.90370.2008)
- 39↑
Kuraitis D, Berardinelli MG, Suuronen EJ, & Musarò A. A necrotic stimulus is required to maximize matrix-mediated myogenesis in mice. Disease Models and Mechanisms 2013 6 793–801. (https://doi.org/10.1242/dmm.011072)
- 40↑
Martin PT, Ettinger AJ, & Sanes JR. A synaptic localization domain in the synaptic cleft protein laminin β2 (s-laminin). Science 1995 269 413–416. (https://doi.org/10.1126/science.7618109)
- 41↑
Aydin O, Zhang X, Nuethong S, Pagan-Diaz GJ, Bashir R, Gazzola M, & Saif MTA. Neuromuscular actuation of biohybrid motile bots. PNAS 2019 116 19841–19847. (https://doi.org/10.1073/pnas.1907051116)
- 42↑
Yucesoy CA, Koopman BH, Huijing PA, & Grootenboer HJ. Three-dimensional finite element modeling of skeletal muscle using a two-domain approach: linked fiber-matrix mesh model. Journal of Biomechanics 2002 35 1253–1262. (https://doi.org/10.1016/S0021-9290(0200069-6)
- 43↑
Karczewska-Kupczewska M, Stefanowicz M, Matulewicz N, Nikołajuk A, & Strączkowski M. Wnt signaling genes in adipose tissue and skeletal muscle of humans with different degrees of insulin sensitivity. Journal of Clinical Endocrinology and Metabolism 2016 101 3079–3087. (https://doi.org/10.1210/jc.2016-1594)
- 44↑
Ruggiero AD, Davis A, Sherrill C, Westwood B, Hawkins GA, Palmer ND, Chou JW, Reeves T, Cox LA, & Kavanagh K. Skeletal muscle extracellular matrix remodeling with worsening glycemic control in nonhuman primates. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 2021 320 R226–R235. (https://doi.org/10.1152/ajpregu.00240.2020)
- 45↑
Richter K, Konzack A, Pihlajaniemi T, Heljasvaara R, & Kietzmann T. Redox-fibrosis: impact of TGF β1 on ROS generators, mediators and functional consequences. Redox Biology 2015 6 344–352. (https://doi.org/10.1016/j.redox.2015.08.015)
- 46↑
Kang L, Ayala JE, Lee-Young RS, Zhang Z, James FD, Neufer PD, Pozzi A, Zutter MM, & Wasserman DH. Diet-induced muscle insulin resistance is associated with extracellular matrix remodeling and interaction with integrin alpha2beta1 in mice. Diabetes 2011 60 416–426. (https://doi.org/10.2337/db10-1116)
- 47↑
Kang L, Mayes WH, James FD, Bracy DP, & Wasserman DH. Matrix metalloproteinase 9 opposes diet-induced muscle insulin resistance in mice. Diabetologia 2014 57 603–613. (https://doi.org/10.1007/s00125-013-3128-1)
- 48↑
Kang L, Lantier L, Kennedy A, Bonner JS, Mayes WH, Bracy DP, Bookbinder LH, Hasty AH, Thompson CB, & Wasserman DH. Hyaluronan accumulates with high-fat feeding and contributes to insulin resistance. Diabetes 2013 62 1888–1896. (https://doi.org/10.2337/db12-1502)
- 49↑
Chajara A, Raoudi M, Delpech B, Leroy M, Basuyau JP, & Levesque H. Increased hyaluronan and hyaluronidase production and hyaluronan degradation in injured aorta of insulin-resistant rats. Arteriosclerosis, Thrombosis, and Vascular Biology 2000 20 1480–1487. (https://doi.org/10.1161/01.ATV.20.6.1480)
- 50↑
Bisht B, Goel HL, & Dey CS. Focal adhesion kinase regulates insulin resistance in skeletal muscle. Diabetologia 2007 50 1058–1069. (https://doi.org/10.1007/s00125-007-0591-6)
- 51↑
Huang D, Khoe M, Ilic D, & Bryer-Ash M. Reduced expression of focal adhesion kinase disrupts insulin action in skeletal muscle cells. Endocrinology 2006 147 3333–3343. (https://doi.org/10.1210/en.2005-0382)
- 52↑
Bisht B, Srinivasan K, & Dey CS. In vivo inhibition of focal adhesion kinase causes insulin resistance. Journal of Physiology 2008 586 3825–3837. (https://doi.org/10.1113/jphysiol.2008.157107)
- 53↑
Bisht B, & Dey CS. Focal adhesion kinase contributes to insulin-induced actin reorganization into a mesh harboring glucose transporter-4 in insulin resistant skeletal muscle cells. BMC Cell Biology 2008 9 48. (https://doi.org/10.1186/1471-2121-9-48)
- 54↑
Richardson DK, Kashyap S, Bajaj M, Cusi K, Mandarino SJ, Finlayson J, DeFronzo RA, Jenkinson CP, & Mandarino LJ. Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle. Journal of Biological Chemistry 2005 280 10290–10297. (https://doi.org/10.1074/jbc.M408985200)
- 55↑
Berria R, Wang L, Richardson DK, Finlayson J, Belfort R, Pratipanawatr T, De Filippis EA, Kashyap S, & Mandarino LJ. Increased collagen content in insulin-resistant skeletal muscle. American Journal of Physiology. Endocrinology and Metabolism 2006 290 E560–E565. (https://doi.org/10.1152/ajpendo.00202.2005)
- 56↑
Watts R, McAinch AJ, Dixon JB, O’Brien PE, & Cameron-Smith D. Increased Smad signaling and reduced MRF expression in skeletal muscle from obese subjects. Obesity 2013 21 525–528. (https://doi.org/10.1002/oby.20070)
- 57↑
Hittel DS, Berggren JR, Shearer J, Boyle K, & Houmard JA. Increased secretion and expression of myostatin in skeletal muscle from extremely obese women. Diabetes 2009 58 30–38. (https://doi.org/10.2337/db08-0943)
- 58↑
Tam CS, Covington JD, Bajpeyi S, Tchoukalova Y, Burk D, Johannsen DL, Zingaretti CM, Cinti S, & Ravussin E. Weight gain reveals dramatic increases in skeletal muscle extracellular matrix remodeling. Journal of Clinical Endocrinology and Metabolism 2014 99 1749–1757. (https://doi.org/10.1210/jc.2013-4381)
- 59↑
Tam CS, Chaudhuri R, Hutchison AT, Samocha-Bonet D, & Heilbronn LK. Skeletal muscle extracellular matrix remodeling after short-term overfeeding in healthy humans. Metabolism: Clinical and Experimental 2017 67 26–30. (https://doi.org/10.1016/j.metabol.2016.10.009)
- 60↑
Graae AS, Grarup N, Ribel-Madsen R, Lystbæk SH, Boesgaard T, Staiger H, Fritsche A, Wellner N, Sulek K, Kjolby M, et al.ADAMTS9 regulates skeletal muscle insulin sensitivity through extracellular matrix alterations. Diabetes 2019 68 502–514. (https://doi.org/10.2337/db18-0418)
