Caveolin-3 promotes glycometabolism, growth and proliferation in muscle cells

Abstract

ObjectiveCaveolin-3 (CAV3) protein is known to be expressed specifically in various myocytes, but its physiological function remains unclear. CAV3, located at the cell membrane, may promote the sensitivity of the Akt signaling pathway, which is closely related to glucose metabolism and to cell growth and proliferation.MethodsThe CAV3 gene was stably transfected into C2C12 muscle cells, and the effects were evaluated by biochemical assays, WB and confocal microscopy for the observation of cellular glucose metabolism, growth and proliferation, and the effect of CAV3 on the Akt signaling pathway with no insulin stimulation.ResultsAfter C2C12 cells were transfected with the mouse CAV3 gene, which increased CAV3 expression, the abundance of the CAV3 and GLUT4 proteins on the cell membrane increased, but the total GLUT4 protein content of the cell was unchanged. Glucose uptake was increased, and this did not affect the glycogen synthesis, but the cell surface area and cell proliferation increased. While there were significant increases in p-Akt and p-p70s6K, which is a downstream component of Akt signaling, the level of GSK3β protein, another component of Akt signaling did not change.ConclusionsThe muscle, CAV3 protein can activate Akt signaling, increase GLUT4 protein localization in the cell membrane, increase glucose uptake, and promote myocyte growth and proliferation. CAV3 protein has a physiological role in glycometabolism, growth and proliferation, independent of insulin stimulation.

A Role for Caveolin-3 in the Pathogenesis of Muscular Dystrophies

“…The Caveolin-3 also interacts with phosphofructokinase-M (PFK-M), a key enzyme in the control of glycolysis in a glucose dependent manner, and may play a role in the regulation of energy metabolism in skeletal muscle fibers [ 90 ]. Shang et al [ 91 ] have shown that in skeletal muscle cell line C2C12, Cav3 protein can activate Akt signaling and increase glucose transporter type 4 (GLUT4) localization at the cell surface, leading to increased glucose uptake. This in turn promotes myocytes’ growth and proliferation.…”

Effect of type 2 diabetes mellitus caveolin‑3 K15N mutation on glycometabolism

“…The K15N mutation reduces the CAV3 protein on the muscle cell membranes by ~95% (32). This reduction causes the abnormal localization of proto-oncogene tyrosine-protein kinase Src on the Golgi (33) and leads to CAV3 protein retention (15). Consistent with these data, western blot analysis performed in the current study indicated that the CAV3 K15N mutation led to decreased recombinant CAV3 protein expression in muscle cells.…”

“…However, IR and GLUT-4 are associated with glucose metabolism and are localized to membrane caveolae, with their expression being regulated by CAV3 on the cell membrane. CAV3 can enhance the expression of IR (38–40) by stimulating IR kinase activity, increasing the stability of IR at the sarcolemmal membrane and reducing its degradation (12), stimulating the phosphorylation of IRS-1 and activating the PI3K/AKT signaling pathway (15,18). Activated AKT not only promoted the translocation of GLUT-4 to the plasma membrane and enhanced glucose uptake, but also induced the phosphorylation of GSK3β, which leads to glycogen synthesis via the activation of glycogen synthase (41,42).…”

“…The results of full-gene scans indicated that the total number of gene variations in the CAV3 gene in patients with T2DM was 48%, compared with 7% in healthy patients (14). A previous study also assessed the transfection of wild-type CAV3 (WT) in muscle cells and found that the PI3K/AKT signaling pathway were activated, increasing the plasma membrane localization of glucose transporter type 4 (GLUT-4) and increasing glucose uptake, cell growth and proliferation (15). One mutation of the CAV3 gene (P104L) in patients with myasthenia has been revealed to be associated with the inhibition of insulin-stimulated glucose uptake and glycogen synthesis in myocytes (16).…”

The Lands cycle modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

“…Overexpression of dominant-negative cav3 leads to decreased glucose uptake and glycogen synthesis in C2C12 cells, which is attributed to decreased Akt phosphorylation (43–45). Conversely, an increase in wildtype cav3 expression is sufficient to enhance Akt phosphorylation and glucose uptake (46). Indeed, LPCAT3 knockdown substantially increased cav3 content in C2C12 myotubes (Figure 5A).…”