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

• Published in: Journal of applied physiology (1985) 2005-12, Vol.99 (6), p.2181-2188
• Main Authors: Hilder, Thomas L, Baer, Lisa A, Fuller, Patrick M, Fuller, Charles A, Grindeland, Richard E, Wade, Charles E, Graves, Lee M
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases; Animals; Biological and medical sciences; Enzymes; Fundamental and applied biological sciences. Psychology; Glucose; Glucose - metabolism; Hindlimb Suspension - methods; Insulin; Insulin - metabolism; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; MAP Kinase Kinase 4 - metabolism; MAP Kinase Signaling System; Multienzyme Complexes - metabolism; Muscle, Skeletal - metabolism; Muscular Atrophy - metabolism; Muscular system; Phosphoproteins - metabolism; Protein-Serine-Threonine Kinases - metabolism; Proteins; Rats; Rats, Sprague-Dawley; Rodents; Signal Transduction
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/japplphysiol.00743.2005

1 Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina; 2 Life Sciences Division, National Aeronautics and Space Administration Ames Research Center, Moffett Field; and 3 Section of Neurobiology, Physiology and Behavior, University of California, Davis, California Submitted 23 June 2005 ; accepted in final form 27 July 2005 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. adenosine 5'-monophosphate-activated protein kinase; hindlimb suspension; c-Jun NH 2 -terminal kinase; mitogen-activated protein kinase Address for reprint requests and other correspondence: L. M. Graves, Dept. of Pharmacology, Univ. of North Carolina, CB #7365, Chapel Hill, NC 27599-7365 (e-mail: lmg{at}med.unc.edu )