Insulin resistance in skeletal muscles of caveolin-3-null mice
Jin Oshikawa1, Koji Otsu, Yoshiyuki Toya
1Departments of Physiology and Medicine, Yokohama City University School of Medicine, 3-9 Fukuura Kanazawa, Yokohama 236-0004, Japan.
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 beta cell toxin, suggesting that the mice were susceptible to severe diabetes in the presence of an additional risk factor. Insulin-stimulated 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.
Insights
Caveolin-3 (Cav3) deficiency causes insulin resistance in skeletal muscles, impairing glucose uptake and metabolism. Restoring Cav3 function improved insulin signaling, highlighting its crucial role in muscle health.
Area of Science:
- Biochemistry
- Molecular Biology
- Endocrinology
Background:
- Type 2 diabetes is characterized by insulin resistance, primarily affecting skeletal muscle insulin action.
- Caveolin-3 (Cav3) is a muscle-specific protein involved in membrane dynamics.
- Previous research suggested Cav3 might inhibit growth, but its role in insulin signaling was unclear.
Purpose of the Study:
- To investigate the role of Caveolin-3 (Cav3) in insulin resistance and signaling within skeletal muscles.
- To determine if Cav3 acts as a scaffolding molecule for insulin receptors.
Main Methods:
- Studied Cav3 null mice to assess insulin resistance markers (glucose uptake, glucose tolerance, serum lipids).
- Examined insulin signaling pathways (insulin receptor, IRS-1, Akt) in skeletal muscle and liver.
- Utilized genetic transfer via needle injection to restore Cav3 expression in skeletal muscles.
Main Results:
- Cav3 null mice exhibited significant insulin resistance, including decreased glucose uptake and impaired glucose tolerance.
- Insulin-stimulated activation of key signaling molecules (IRS-1, Akt) was reduced in the skeletal muscles of Cav3 null mice.
- Restoration of Cav3 in skeletal muscles normalized insulin signaling pathways.
Conclusions:
- Caveolin-3 (Cav3) plays a critical role in enhancing insulin signaling in skeletal muscles.
- Cav3 does not function as a scaffolding molecule for insulin receptors in this context.
- Cav3 deficiency contributes to insulin resistance, suggesting therapeutic potential.
