Insulin-independent pathways mediating glucose uptake in hindlimb-suspended skeletal muscle

Abstract

Insulin resistance accompanies atrophy in slow-twitch skeletal muscles such as the soleus. Using a rat hindlimb suspension model of atrophy, we have previously shown that an upregulation of JNK occurs in atrophic muscles and correlates with the degradation of insulin receptor substrate-1 (IRS-1) (Hilder TL, Tou JC, Grindeland RF, Wade CE, and Graves LM. FEBS Lett 553: 63-67, 2003), suggesting that insulin-dependent glucose uptake may be impaired. However, during atrophy, these muscles preferentially use carbohydrates as a fuel source. To investigate this apparent dichotomy, we examined insulin-independent pathways involved in glucose uptake following a 2- to 13-wk hindlimb suspension regimen. JNK activity was elevated throughout the time course, and IRS-1 was degraded as early as 2 wk. AMP-activated protein kinase (AMPK) activity was significantly higher in atrophic soleus muscle, as were the activities of the ERK1/2 and p38 MAPKs. As a comparison, we examined the kinase activity in solei of rats exposed to hypergravity conditions (2 G). IRS-1 phosphorylation, protein, and AMPK activity were not affected by 2 G, demonstrating that these changes were only observed in soleus muscle from hindlimb-suspended animals. To further examine the effect of AMPK activation on glucose uptake, C2C12 myotubes were treated with the AMPK activator metformin and then challenged with the JNK activator anisomycin. While anisomycin reduced insulin-stimulated glucose uptake to control levels, metformin significantly increased glucose uptake in the presence of anisomycin and was independent of insulin. Taken together, these results suggest that AMPK may be an important mediator of insulin-independent glucose uptake in soleus during skeletal muscle atrophy.

Acute Diabetes Moderates Trafficking of Cardiac Lipoprotein Lipase Through p38 Mitogen-Activated Protein Kinase–Dependent Actin Cytoskeleton Organization

“…A different approach used thrombin to activate p38 MAPK. It should be noted that the more traditional methods to activate p38 MAPK include sorbitol and anisomycin; however, sorbitol is also known to activate AMPK (52), whereas anisomycin is shown to cause insulin resistance (53). Thrombin, without affecting AMPK phosphorylation, had a robust effect to provoke cardiomyocyte p38 MAPK, likely through proteinase-activated receptor 4 and c-Src tyrosine kinase activation (54).…”

The soybean peptide aglycin regulates glucose homeostasis in type 2 diabetic mice via IR/IRS1 pathway

“…GLUT4 can translocate to the cell membrane where it inserted, and results in the facilitated glucose uptake [33]. However, GLUT4 translocation could be impaired in the diabetic skeletal muscle followed by the reduction of autophosphorylation or substrate phosphorylation of the IR kinase, IRS1 and Akt [34][35][36][37].…”

Insights into muscle atrophy and recovery pathway based on genetic models

“…MuRF2 is also a protein with interesting properties. It is involved in primary myogenesis [11][12][13] and can shuttle between cytosol and the nucleus under atrophic conditions. Furthermore, the closely related MuRF1 has been implicated in the ubiquitin-controlled protein turnover in atrophied muscle [2 ].…”