Insulin resistance in skeletal muscles of caveolin-3-null mice

Abstract

Type 2 diabetes is preceded by the development of insulin resistance, in which the action of insulin is impaired, largely in skeletal muscles. Caveolin-3 (Cav3) is a muscle-specific subtype of caveolin, an example of a scaffolding protein found within membranes. Cav is also known as growth signal inhibitor, although it was recently demonstrated that the genetic disruption of Cav3 did not augment growth in mice. We found, however, that the lack of Cav3 led to the development of insulin resistance, as exemplified by decreased glucose uptake in skeletal muscles, impaired glucose tolerance test performance, and increases in serum lipids. Such impairments were markedly augmented in the presence of streptozotocin, a pancreatic ␤ cell toxin, suggesting that the mice were susceptible to severe diabetes in the presence of an additional risk factor. Insulinstimulated activation of insulin receptors and downstream molecules, such as IRS-1 and Akt, was attenuated in the skeletal muscles of Cav3 null mice, but not in the liver, without affecting protein expression or subcellular localization. Genetic transfer of Cav3 by needle injection restored insulin signaling in skeletal muscles. Our findings suggest that Cav3 is an enhancer of insulin signaling in skeletal muscles but does not act as a scaffolding molecule for insulin receptors. Diabetes mellitus comprises a group of common metabolic disorders that share the phenotype of hyperglycemia (1). In particular, adult-onset diabetes, or type 2 diabetes, is a heterogeneous group of disorders usually characterized by varying degrees of insulin resistance and increased blood glucose concentrations. Insulin binding to insulin receptors (IR) evokes a cascade of phosphorylation events, as commonly seen in other growth factor signaling, beginning with the autophosphorylation of IR in multiple tyrosyl residues, followed by downstream signaling events (2). The combined actions of these events mediate the biological effects of insulin, leading to increased glucose uptake.Caveolin (Cav) is a major protein component of caveolae, flask-shaped plasma membrane invaginations found in myocytes, endothelial cells, fibroblasts, and adipocytes (for review, see ref.3). Numerous studies have indicated that Cav works as a scaffolding molecule; it binds directly to various receptors and their effector molecules and anchors these molecules to the caveolae. More important, Cav inhibits the function of these molecules. Cav-1 (Cav1)-mediated inhibition, by the use of a short stretch of the amino terminus domain of Cav (or the Cav scaffolding domain peptide), has been demonstrated with various kinases involved in cellular growth, such as receptor tyrosine kinases, e.g., epidermal growth factor-R (4) or platelet-derived growth factor-R (5), as well as protein kinase C (6) or Src (7). These studies have demonstrated that the Cav1 peptide directly bound to these molecules and inhibited their activity. Accordingly, it is now believed that Cav1 is an inhibitor of cellular growth signal (8-10).Cav3 is the newest...

Identification and modulation of a caveolae-dependent signal pathway that regulates plasminogen activator inhibitor-1 in insulin-resistant adipocytes

“…This suggests that cholesterol depletion and, presumably, consequent caveolar dysfunction would lead to insulin resistance. Consistently, it was recently reported that caveolin-1 Ϫ/Ϫ and caveolin-3 Ϫ/Ϫ mice, both known to have a dramatic reduction in caveolae, exhibit insulin resistance (38,39). Moreover, in adipocytes treated with TNF-␣, the IR accumulated less in the detergent-insoluble low-density membrane fractions (microdomains) and shifted to the high-density fractions, suggesting a translocation of IR from caveolar to noncaveolar fractions (40).…”

Time‐dependent regulation of muscle caveolin activation and insulin signalling in response to high‐fat diet

“…In skeletal muscle, the protein expression of IR and other molecules involved in insulin signalling are unaltered, whereas phosphorylation of IR, IRS or Akt/PKB are all attenuated and insulin-stimulated glucose uptake is decreased [8].…”

“…Thus, there is considerable evidence of caveolin involvement in the modulation of insulin signalling and therefore in the regulation of the intermediary metabolism, which becomes altered in obesity, and associated with metabolic disorders such as insulin resistance and type 2 diabetes [7]. For instance, Cav-3 deficient mice develop late-onset obesity accompanied by insulin resistance in key peripheral tissues and abnormal lipid metabolism [8,9]. Therefore, it is clear that caveolins may play an important regulatory role in muscle insulin signalling.…”

Dexamethasone downregulates caveolin-1 causing muscle atrophy via inhibited insulin signaling

“…Thus, CAV3 deficiency due to mutations in the gene causes the degeneration of myofibrils, leading to skeletal muscle diseases (Gazzerro et al 2010). Results of functional analyses of CAV3-null mice indicated that CAV3 is an enhancer of insulin signaling (Oshikawa et al 2004). In addition, CAV3 inhibits myostatin signaling through its interaction with ALK5, resulting in increased myofiber size (Ohsawa et al 2004).…”