PPARδ activator GW-501516 has no acute effect on glucose transport in skeletal muscle

2006 ◽  
Vol 290 (4) ◽  
pp. E607-E611 ◽  
Author(s):  
Shin Terada ◽  
Scott Wicke ◽  
John O. Holloszy ◽  
Dong-Ho Han
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Transport ◽  
Insulin Action ◽  
Uncoupling Protein ◽  
Mitogen Activated Protein Kinase ◽  
Peroxisome Proliferator ◽  
Direct Stimulation ◽  
Cultured Myotubes ◽  
Stimulation Of

It has been reported that treatment of cultured human skeletal muscle myotubes with the peroxisome proliferator-activated receptor-δ (PPARδ) activator GW-501516 directly stimulates glucose transport and enhances insulin action. Cultured myotubes are minimally responsive to insulin stimulation of glucose transport and are not a good model for studying skeletal muscle glucose transport. The purpose of this study was to evaluate the effect of GW-501516 on glucose transport to determine whether the findings on cultured myotubes have relevance to skeletal muscle. Rat epitrochlearis and soleus muscles were treated for 6 h with 10, 100, or 500 nM GW-501516, followed by measurement of 2-deoxyglucose uptake. GW-501516 had no effect on glucose uptake. There was no effect on insulin sensitivity or responsiveness. Also, in contrast to findings on myotubes, treatment of muscles with GW-501516 did not result in increased phosphorylation or increased expression of AMP-activated protein kinase (AMPK) or p38 mitogen-activated protein kinase (MAPK). Treatment of epitrochlearis muscles with GW-501516 for 24 h induced a threefold increase in uncoupling protein-3 mRNA, providing evidence that the GW-501516 compound that we used gets into and is active in skeletal muscle. In conclusion, our results show that, in contrast to myotubes in culture, skeletal muscle does not respond to GW-501516 with 1) an increase in AMPK or p38 MAPK phosphorylation or expression or 2) direct stimulation of glucose transport or enhanced insulin action.

Characterization of the role of the AMP-activated protein kinase in the stimulation of glucose transport in skeletal muscle cells

2002 ◽  
Vol 363 (1) ◽  
pp. 167-174 ◽  
Author(s):  
Lee G.D. FRYER ◽  
Fabienne FOUFELLE ◽  
Kay BARNES ◽  
Stephen A. BALDWIN ◽  
Angela WOODS ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Phorbol Ester ◽  
Hyperosmotic Stress ◽  
Amp Activated Protein Kinase ◽  
Stimulation Of ◽  
Constitutively Active

Stimulation of AMP-activated protein kinase (AMPK) in skeletal muscle has been correlated with an increase in glucose transport. Here, we demonstrate that adenoviral-mediated expression of a constitutively active mutant of AMPKα leads to activation of glucose transport in a skeletal-muscle cell line, similar to that seen following treatment with 5-amino-imidazolecarboxamide (AICA) riboside, hyperosmotic stress or insulin. In contrast, expression of a dominant-negative form of AMPK blocked the stimulation of glucose transport by both AICA riboside and hyperosmotic stress, but was without effect on either insulin or phorbol-ester-stimulated transport. These results demonstrate that activation of AMPK is sufficient for stimulation of glucose uptake into muscle cells, and is a necessary component of the AICA riboside- and hyperosmotic-stress-induced pathway leading to increased glucose uptake. On the other hand, AMPK is not required in the insulin- or phorbol-ester-mediated pathways. Long-term (5 days) expression of the constitutively active AMPK mutant increased protein expression of GLUT1, GLUT4 and hexokinase II, consistent with previous reports on the chronic treatment of rats with AICA riboside. Expression of constitutively active AMPK had no detectable effect on p38 mitogen-activated protein kinase levels, although interestingly the level of protein kinase B was decreased. These results demonstrate that long-term activation of AMPK is sufficient to cause increased expression of specific proteins in muscle. Our results add further support to the hypothesis that long-term activation of AMPK is involved in the adaptive response of muscle to exercise training.

Phenylarsine oxide and denervation effects on hormone-stimulated glucose transport

1988 ◽  
Vol 255 (2) ◽  
pp. E159-E165 ◽  
Author(s):  
M. O. Sowell ◽  
K. A. Robinson ◽  
M. G. Buse
Keyword(s):  
Skeletal Muscle ◽  
Glucose Transport ◽  
Insulin Action ◽  
Denervated Muscle ◽  
Phenylarsine Oxide ◽  
Early Step ◽  
Factor I ◽  
Igf I ◽  
Receptor Number ◽  
Stimulation Of

Insulin and insulin-like growth factor I (IGF-I) stimulate glucose transport in skeletal muscle through separate receptors. The proximal postreceptor events in coupling insulin and IGF-I receptors to glucose transport have been suggested to differ. Denervation of skeletal muscle produces a postreceptor insulin resistance presumably at an early step in the signaling cascade. We examined the effects of denervation and phenylarsine oxide (PAO), an agent believed to block insulin action on transport at a postreceptor step, on insulin and IGF-I stimulated 2-deoxy-D-glucose transport in isolated solei. Denervation (24 h) produced severe IGF-I resistance without affecting IGF-I receptor number or affinity. PAO inhibited insulin and IGF-I stimulation of transport in control muscles by approximately 90 and approximately 70%, respectively. In denervated muscle PAO inhibited transport stimulation by both hormones less than in controls. Conclusions are that 1) skeletal muscle insulin and IGF-I receptors signal transport mainly through a PAO-sensitive mechanism, but IGF-I's action involves a larger PAO-resistant component; 2) the denervation-induced postreceptor resistance of glucose transport to both hormones involves primarily the PAO-sensitive pathway.

Mechanisms of calcium-induced mitochondrial biogenesis and GLUT4 synthesis

2007 ◽  
Vol 32 (5) ◽  
pp. 840-845 ◽  
Author(s):  
David C. Wright
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Mitochondrial Biogenesis ◽  
Glucose Transporter ◽  
Mitochondrial Protein ◽  
Mitogen Activated Protein Kinase ◽  
Peroxisome Proliferator ◽  
Adaptive Responses ◽  
Peroxisome Proliferator Activated Receptor ◽  
Skeletal Muscle Insulin Resistance

Regularly performed aerobic exercise leads to increases in skeletal muscle mitochondria and glucose transporter 4 (GLUT4) protein content, resulting in an enhanced capacity to oxidize substrates and improvements in insulin- and contraction-mediated glucose uptake. Although the specific mechanisms governing these adaptive responses have not been fully elucidated, accumulating evidence suggests that the increase in cytosolic Ca2+ that occurs with each wave of sacrolemmal depolarization is a key component of these processes. Treating L6 muscle cells with agents that increase Ca2+ without causing reductions in ~P or the activation of 5′-AMP-activated protein kinase leads to increases in GLUT4 and mitochondrial protein contents. This effect is likely controlled through calcium/calmodulin-dependent protein kinase (CaMK), since KN93, a specific CaMK inhibitor, blocks these adaptive responses. Recent findings provide evidence that the activation of p38 mitogen-activated protein kinase (MAPK) is involved in the pathway through which Ca2+/CaMK mediates mitochondrial and GLUT4 biogenesis. p38 MAPK initiates GLUT4 and mitochondrial biogenesis through the activation      of transcription factors and transcriptional coactivators such as myocyte enhancer factor 2 (MEF2) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). Subsequent increases in the content of these proteins further enhance Ca2+-induced GLUT4 and mitochondrial biogenesis. Since decreases in mitochondrial and GLUT4 contents are associated with skeletal muscle insulin resistance, an understanding of the mechanisms by which these processes can be normalized will aid in the prevention and treatment of type 2 diabetes.

scholarly journals Characterization of the role of the AMP-activated protein kinase in the stimulation of glucose transport in skeletal muscle cells

2002 ◽  
Vol 363 (1) ◽  
pp. 167 ◽  
Author(s):  
Lee G. D. FRYER ◽  
Fabienne FOUFELLE ◽  
Kay BARNES ◽  
Stephen A. BALDWIN ◽  
Angela WOODS ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Transport ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Amp Activated Protein Kinase ◽  
Stimulation Of

scholarly journals Troglitazone Effects on Gene Expression in Human Skeletal Muscle of Type II Diabetes Involve Up-Regulation of Peroxisome Proliferator-Activated Receptor-γ1

1998 ◽  
Vol 83 (8) ◽  
pp. 2830-2835 ◽  
Author(s):  
Kyong Soo Park ◽  
Theodore P. Ciaraldi ◽  
Kristin Lindgren ◽  
Leslie Abrams-Carter ◽  
Sunder Mudaliar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Type Ii Diabetes ◽  
Insulin Action ◽  
Peroxisome Proliferator ◽  
Type Ii ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nondiabetic Control ◽  
Muscle Cultures ◽  
Stimulation Of

abstract Troglitazone, besides improving insulin action in insulin-resistant subjects, is also a specific ligand for the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ). To determine whether troglitazone might enhance insulin action by stimulation of PPARγ gene expression in muscle, total PPARγ messenger RNA (mRNA), and protein were determined in skeletal muscle cultures from nondiabetic control and type II diabetic subjects before and after treatment of cultures with troglitazone (4 days ± troglitazone, 11.5μ m). Troglitazone treatment increased PPARγ mRNA levels up to 3-fold in muscle cultures from type II diabetics (277 ± 63 to 630 ± 100 × 103 copies/μg total RNA, P = 0.003) and in nondiabetic control subjects (200 ± 42 to 490 ± 81, P = 0.003). PPARγ protein levels in both diabetic (4.7 ± 1.6 to 13.6± 3.0 AU/10 μg protein, P < 0.02) and nondiabetic cells (7.4 ± 1.0 to 12.7 ± 1.8, P < 0.05) were also up-regulated by troglitazone treatment. Increased PPARγ was associated with stimulation of human adipocyte lipid binding protein (ALBP) and muscle fatty acid binding protein (mFABP) mRNA, without change in the mRNA for glycerol-3-phosphate dehydrogenase, PPARδ, myogenin, uncoupling protein-2, or sarcomeric α-actin protein. In summary, we showed that troglitazone markedly induces PPARγ, ALBP, and mFABP mRNA abundance in muscle cultures from both nondiabetic and type II diabetic subjects. Increased expression of PPARγ protein and other genes involved in glucose and lipid metabolism in skeletal muscle may account, in part, for the insulin sensitizing effects of troglitazone in type II diabetes.

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