Activation of p38 mitogen-activated protein kinase alpha and beta by insulin and contraction in rat skeletal muscle: potential role in the stimulation of glucose transport.

Abstract

The stress-activated p38 mitogen-activated protein kinase (MAPK) was recently shown to be activated by insulin in muscle and adipose cells in culture. Here, we explore whether such stimulation is observed in rat skeletal muscle and whether muscle contraction can also affect the enzyme. Insulin injection (2 U over 3.5 min) resulted in increases in p38 MAPK phosphorylation measured in soleus (3.2-fold) and quadriceps (2.2-fold) muscles. Increased phosphorylation (3.5-fold) of an endogenous substrate of p38 MAPK, cAMP response element binder (CREB), was also observed. After in vivo insulin treatment, p38 MAPK␣ and p38 MAPK␤ isoforms were found to be activated (2.1-and 2.4-fold, respectively), using an in vitro kinase assay, in immunoprecipitates from quadriceps muscle extracts. In vitro insulin treatment (1 nmol/l over 4 min) and electrically-induced contraction of isolated extensor digitorum longus (EDL) muscle also doubled the kinase activity of p38 MAPK␣ and p38 MAPK␤. The activity of both isoforms was inhibited in vitro by 10 µmol/l SB203580 in all muscles. To explore the possible participation of p38 MAPK in the stimulation of glucose uptake, EDL and soleus muscles were exposed to increasing doses of SB203580 before and during stimulation by insulin or contraction. SB203580 caused a significant reduction in the insulin-or contractionstimulated 2-deoxyglucose uptake. Maximal inhibition (50-60%) occurred with 10 µmol/l SB203580. These results show that p38 MAPK␣ and -␤ isoforms are activated by insulin and contraction in skeletal muscle. The data further suggest that activation of p38 MAPK may participate in the stimulation of glucose uptake by both stimuli in rat skeletal muscle.

Stimulation of glucose uptake by chronic vanadate pretreatment in cardiomyocytes requires PI 3-kinase and p38 MAPK activation

“…This is comparable to what has been observed after p38 MAPK inhibition with SB-203580 in 3T3-L1, L6 muscle cells, and isolated soleus muscle (36,40). Furthermore, inhibition of the enzyme with a dominant negative mutant of p38 MAPK also diminished the insulin-stimulated glucose uptake by 40% (34).…”

“…Recent studies have suggested that p38 MAPK is a key signaling intermediate in the regulation of glucose transport by insulin (34,36,40). We therefore determined whether vanadate regulates this enzyme in cardiomyocytes.…”

“…In addition to the IRS-1/PI 3-kinase pathway, insulin also activates p38 MAPK. Recent data suggest that this enzyme modulates the intrinsic activity of GLUT4 and, thus, the stimulation of glucose uptake by insulin in skeletal muscle (36) and 3T3-L1 adipocytes (34,40). In contrast, vanadate-mediated glucose uptake has been shown to be independent of p38 MAPK activation (43).…”

Disruption of Cortical Actin in Skeletal Muscle Demonstrates an Essential Role of the Cytoskeleton in Glucose Transporter 4 Translocation in Insulin-sensitive Tissues

“…However, the fact that insulin did not alter plasma membrane GLUT1 levels makes it difficult to reconcile how this transporter isoform could fully account for this discrepancy. In the same context, there is also significant evidence that insulin and other stimuli can alter the activity of GLUT4 transporters (61,62). Thus, the ability of insulin to stimulate the "intrinsic activity" of the basal pool of GLUT4 in the plasma membrane may not be dependent on cortical F-actin.…”

Renal p38 MAP kinase activity in experimental diabetes

“…Insulin per se activates p38 MAPK in the VSMC 29 and other cell types. [30][31][32] This suggests that interactions between hyperglycemia, insulin levels, and the p38 pathway activity may be more complex. This issue is even more relevant with respect to the fact that previous experimental in vivo studies were performed in diabetic animals without insulin treatment.…”