Enhanced insulin action on glucose transport and insulin signaling in 7-day unweighted rat soleus muscle

Hindlimb suspension (HS), a model of simulated weightlessness, enhances insulin action on glucose transport in unweighted rat soleus muscle. In the present study, we tested the hypothesis that these changes in glucose transport in 3- and 7-day HS soleus of juvenile, female Sprague-Dawley rats were due to increased functionality of insulin signaling factors, including insulin receptor (IR), IR substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3-kinase), and Akt. Insulin-stimulated (2 mU/ml) glucose transport was significantly ( P < 0.05) enhanced in 3- and 7-day HS soleus by 59 and 113%, respectively, compared with weight-bearing controls. Insulin-stimulated tyrosine phosphorylation of IR and Ser473 phosphorylation of Akt was not altered by unweighting. Despite decreased (34 and 64%) IRS-1 protein in 3- and 7-day HS soleus, absolute insulin-stimulated tyrosine phosphorylation of IRS-1 was not diminished, indicating relative increases in IRS-1 phosphorylation of 62 and 184%, respectively. In the 7-day HS soleus, this was accompanied by increased (47%) insulin-stimulated IRS-1 associated with the p85 subunit of PI3-kinase. Interestingly, the enhanced insulin-stimulated glucose transport in the unweighted soleus was not completely inhibited (89–92%) by wortmannin, a PI3-kinase inhibitor. Finally, protein expression and activation of p38 MAPK, a stress-activated serine/threonine kinase associated with insulin resistance, was decreased by 32 and 18% in 7-day HS soleus. These results indicate that the increased insulin action on glucose transport in the 7-day unweighted soleus is associated with increased insulin signaling through IRS-1 and PI3-kinase and decreased p38 MAPK protein expression. However, PI3-kinase-independent mechanisms must also play a small role in this adaptive response to HS.

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Interactions of exercise training and α-lipoic acid on insulin signaling in skeletal muscle of obese Zucker rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00013.2004 ◽

2004 ◽

Vol 287 (3) ◽

pp. E529-E536 ◽

Cited By ~ 61

Author(s):

Vitoon Saengsirisuwan ◽

Felipe R. Perez ◽

Julie A. Sloniger ◽

Thomas Maier ◽

Erik J. Henriksen

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Protein Expression ◽

Glucose Transport ◽

Soleus Muscle ◽

Lipoic Acid ◽

Combination Treatment ◽

Insulin Signaling ◽

Insulin Action ◽

Insulin Resistant

We have shown previously (Saengsirisuwan V, Kinnick TR, Schmit MB, and Henriksen EJ. J Appl Physiol 91: 145–153, 2001) that the antioxidant R-(+)-α-lipoic acid (R-ALA), combined with endurance exercise training (ET), increases glucose transport in insulin-resistant skeletal muscle in an additive fashion. The purpose of the present study was to investigate possible cellular mechanisms responsible for this interactive effect. We evaluated the effects of R-ALA alone, ET alone, or R-ALA and ET in combination on insulin-stimulated glucose transport, protein expression, and functionality of specific insulin-signaling factors in soleus muscle of obese Zucker ( fa/fa) rats. Obese animals remained sedentary, received R-ALA (30 mg·kg body wt−1·day−1), performed ET (daily treadmill running for ≤60 min), or underwent both R-ALA treatment and ET for 15 days. R-ALA or ET individually increased ( P < 0.05) insulin-mediated (5 mU/ml) glucose transport (2-deoxyglucose uptake) in soleus muscle by 45 and 68%, respectively, and this value was increased to the greatest extent (124%) in the combined treatment group. Soleus insulin receptor substrate (IRS)-1 protein was significantly increased by R-ALA alone (30%) or ET alone (31%), and a further enhancement (55%) was observed after the combination treatment in the obese animals. Enhanced levels of IRS-1 protein expression after individual or combined interventions were significantly correlated with insulin action on glucose transport activity ( r = 0.597, P = 0.0055). Similarly, insulin-mediated IRS-1 associated with the p85 regulatory subunit of phosphatidylinositol 3-kinase was increased by R-ALA (317%) and ET (319%) and to the greatest extent (435%) (all P < 0.05) by the combination treatment. These results indicate that the improvements of insulin action in insulin-resistant skeletal muscle after R-ALA or ET, alone and in combination, were associated with increases in IRS-1 protein expression and IRS-1 associated with p85.

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Acute selective glycogen synthase kinase-3 inhibition enhances insulin signaling in prediabetic insulin-resistant rat skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00547.2004 ◽

2005 ◽

Vol 288 (6) ◽

pp. E1188-E1194 ◽

Cited By ~ 63

Author(s):

Betsy B. Dokken ◽

Julie A. Sloniger ◽

Erik J. Henriksen

Keyword(s):

Skeletal Muscle ◽

Tyrosine Phosphorylation ◽

Glucose Transport ◽

Insulin Signaling ◽

Insulin Action ◽

Glycogen Synthase ◽

Serine Phosphorylation ◽

Zucker Rats ◽

Type I ◽

Insulin Resistant

Glycogen synthase kinase-3 (GSK3) has been implicated in the multifactorial etiology of skeletal muscle insulin resistance in animal models and in human type 2 diabetic subjects. However, the potential molecular mechanisms involved are not yet fully understood. Therefore, we determined if selective GSK3 inhibition in vitro leads to an improvement in insulin action on glucose transport activity in isolated skeletal muscle of insulin-resistant, prediabetic obese Zucker rats and if these effects of GSK3 inhibition are associated with enhanced insulin signaling. Type I soleus and type IIb epitrochlearis muscles from female obese Zucker rats were incubated in the absence or presence of a selective, small organic GSK3 inhibitor (1 μM CT118637, Ki < 10 nM for GSK3α and GSK3β). Maximal insulin stimulation (5 mU/ml) of glucose transport activity, glycogen synthase activity, and selected insulin-signaling factors [tyrosine phosphorylation of insulin receptor (IR) and IRS-1, IRS-1 associated with p85 subunit of phosphatidylinositol 3-kinase, and serine phosphorylation of Akt and GSK3] were assessed. GSK3 inhibition enhanced ( P <0.05) basal glycogen synthase activity and insulin-stimulated glucose transport in obese epitrochlearis (81 and 24%) and soleus (108 and 20%) muscles. GSK3 inhibition did not modify insulin-stimulated tyrosine phosphorylation of IR β-subunit in either muscle type. However, in obese soleus, GSK3 inhibition enhanced (all P < 0.05) insulin-stimulated IRS-1 tyrosine phosphorylation (45%), IRS-1-associated p85 (72%), Akt1/2 serine phosphorylation (30%), and GSK3β serine phosphorylation (39%). Substantially smaller GSK3 inhibitor-mediated enhancements of insulin action on these insulin signaling factors were observed in obese epitrochlearis. These results indicate that selective GSK3 inhibition enhances insulin action in insulin-resistant skeletal muscle of the prediabetic obese Zucker rat, at least in part by relieving the deleterious effects of GSK3 action on post-IR insulin signaling. These effects of GSK3 inhibition on insulin action are greater in type I muscle than in type IIb muscle from these insulin-resistant animals.

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Immobilization depresses insulin signaling in skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.279.6.e1235 ◽

2000 ◽

Vol 279 (6) ◽

pp. E1235-E1241 ◽

Cited By ~ 38

Author(s):

Munetaka Hirose ◽

Masao Kaneki ◽

Hiroki Sugita ◽

Shingo Yasuhara ◽

J. A. Jeevendra Martyn

Keyword(s):

Skeletal Muscle ◽

Protein Expression ◽

Insulin Receptor ◽

Tyrosine Phosphorylation ◽

Glucose Transport ◽

Insulin Signaling ◽

Regulatory Subunit ◽

Protein Levels ◽

Essential Components ◽

Prolonged Immobilization

Prolonged immobilization depresses insulin-induced glucose transport in skeletal muscle and leads to a catabolic state in the affected areas, with resultant muscle wasting. To elucidate the altered intracellular mechanisms involved in the insulin resistance, we examined insulin-stimulated tyrosine phosphorylation of the insulin receptor β-subunit (IR-β) and insulin receptor substrate (IRS)-1 and activation of its further downstream molecule, phosphatidylinositol 3-kinase (PI 3-K), after unilateral hindlimb immobilization in the rat. The contralateral hindlimb served as control. After 7 days of immobilization of the rat, insulin was injected into the portal vein, and tibialis anterior muscles on both sides were extracted. Immobilization reduced insulin-stimulated tyrosine phosphorylation of IR-β and IRS-1. Insulin-stimulated binding of IRS-1 to p85, the regulatory subunit of PI 3-K, and IRS-1-associated PI 3-K activity were also decreased in the immobilized hindlimb. Although IR-β and p85 protein levels were unchanged, IRS-1 protein expression was downregulated by immobilization. Thus prolonged immobilization may cause depression of insulin-stimulated glucose transport in skeletal muscle by altering insulin action at multiple points, including the tyrosine phosphorylation, protein expression, and activation of essential components of insulin signaling pathways.

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Influence of chronic stretching upon rat soleus muscle during non-weight-bearing conditions

Pflügers Archiv - European Journal of Physiology ◽

10.1007/bf00374323 ◽

1994 ◽

Vol 429 (2) ◽

pp. 274-279 ◽

Cited By ~ 27

Author(s):

Damien Leterme ◽

Corinne Cordonnier ◽

Yvonne Mounier ◽

Maurice Falempin

Keyword(s):

Soleus Muscle ◽

Weight Bearing ◽

Rat Soleus Muscle

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Time course of soleus muscle myosin expression during hindlimb suspension and recovery

Journal of Applied Physiology ◽

10.1152/jappl.1987.63.1.130 ◽

1987 ◽

Vol 63 (1) ◽

pp. 130-137 ◽

Cited By ~ 152

Author(s):

D. B. Thomason ◽

R. E. Herrick ◽

D. Surdyka ◽

K. M. Baldwin

Keyword(s):

Protein Expression ◽

Soleus Muscle ◽

Time Course ◽

Weight Bearing ◽

Relative Proportion ◽

Contractile Protein ◽

Myosin Isoforms ◽

Hindlimb Unweighting ◽

Loss Of Weight ◽

Myofibril Protein

This study examined the time course of adult rodent soleus muscle myofibril and myosin isoform protein expression after 4, 8, 16, 28, and 56 days of hindlimb unweighting by tail suspension (S). The time course of soleus muscle recovery (R) was also examined after 28 days of hindlimb unweighting with an additional 4, 8, 16, and 28 days of unrestricted cage activity. During suspension, soleus muscle myofibril protein rapidly decreased from 34.3 +/- 3.1 (1.96SE) mg/pair in the control (C) group to 6.9 +/- 1.4 (1.96SE) mg/pair in S (t = 56 days). The calculated first-order degradation rate constant for this loss was kd = 0.17 days-1 [half time (t1/2) = 4.1 days]. The estimated slow myosin (SM) isoform content decreased from 13.4 +/- 2.0 (1.96SE) mg/pair in C to 2.1 +/- 0.2 (1.96SE) mg/pair in S (kd = 0.19 days-1, t1/2 = 3.6 days). The relative proportion of other myosin isoforms was increased at 28 and 56 days of suspension, reflecting an apparent de novo synthesis and the loss of SM. Recovery of contractile protein after 28 days of suspension was slower for both the myofibril protein and the SM isoform (kd = 0.07 days-1, t1/2 = 10 days). These data suggest that loss of weight bearing specifically affected the mechanisms of contractile protein expression reflected in soleus muscle protein degradation processes. In addition, the expression of the myosin isoforms were apparently differentially affected by the loss of weight-bearing activity.

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Distribution of myosin heavy chain isoforms in non-weight-bearing rat soleus muscle fibers

Journal of Applied Physiology ◽

10.1152/jappl.1996.81.6.2540 ◽

1996 ◽

Vol 81 (6) ◽

pp. 2540-2546 ◽

Cited By ~ 71

Author(s):

Robert J. Talmadge ◽

Roland R. Roy ◽

V. Reggie Edgerton

Keyword(s):

Myosin Heavy Chain ◽

Soleus Muscle ◽

Heavy Chain ◽

De Novo ◽

Weight Bearing ◽

Muscle Fibers ◽

Myosin Heavy Chain Isoforms ◽

Hindlimb Suspension ◽

Type I ◽

Rat Soleus Muscle

Talmadge, Robert J., Roland R. Roy, and V. Reggie Edgerton.Distribution of myosin heavy chain isoforms in non-weight-bearing rat soleus muscle fibers. J. Appl. Physiol. 81(6): 2540–2546, 1996.—The effects of 14 days of spaceflight (SF) or hindlimb suspension (HS) (Cosmos 2044) on myosin heavy chain (MHC) isoform content of the rat soleus muscle and single muscle fibers were determined. On the basis of electrophoretic analyses, there was a de novo synthesis of type IIx MHC but no change in either type I or IIa MHC isoform proportions after either SF or HS compared with controls. The percentage of fibers containing only type I MHC decreased by 26 and 23%, and the percentage of fibers with multiple MHCs increased from 6% in controls to 32% in HS and 34% in SF rats. Type IIx MHC was always found in combination with another MHC or combination of MHCs; i.e., no fibers contained type IIx MHC exclusively. These data suggest that the expression of the normal complement of MHC isoforms in the adult rat soleus muscle is dependent, in part, on normal weight bearing and that the absence of weight bearing induces a shift toward type IIx MHC protein expression in the preexisting type I and IIa fibers of the soleus.

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Two weeks of metformin treatment induces AMPK-dependent enhancement of insulin-stimulated glucose uptake in mouse soleus muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00417.2013 ◽

2014 ◽

Vol 306 (10) ◽

pp. E1099-E1109 ◽

Cited By ~ 36

Author(s):

Jonas Møller Kristensen ◽

Jonas T. Treebak ◽

Peter Schjerling ◽

Laurie Goodyear ◽

Jørgen F. P. Wojtaszewski

Keyword(s):

Protein Expression ◽

Glucose Uptake ◽

Soleus Muscle ◽

Insulin Signaling ◽

Metformin Treatment ◽

Hexokinase Ii ◽

Ampk Signaling ◽

Amp Activated Protein Kinase ◽

Oral Doses

Metformin-induced activation of the 5′-AMP-activated protein kinase (AMPK) has been associated with enhanced glucose uptake in skeletal muscle, but so far no direct causality has been examined. We hypothesized that an effect of in vivo metformin treatment on glucose uptake in mouse skeletal muscles is dependent on AMPK signaling. Oral doses of metformin or saline treatment were given to muscle-specific kinase dead (KD) AMPKα2 mice and wild-type (WT) littermates either once or chronically for 2 wk. Soleus and extensor digitorum longus muscles were used for measurements of glucose transport and Western blot analyses. Chronic treatment with metformin enhanced insulin-stimulated glucose uptake in soleus muscles of WT (∼45%, P < 0.01) but not of AMPK KD mice. Insulin signaling at the level of Akt protein expression or Thr308 and Ser473 phosphorylation was not changed by metformin treatment. Insulin signaling at the level of Akt and TBC1D4 protein expression as well as Akt Thr308/Ser473 and TBC1D4 Thr642/Ser711 phosphorylation were not changed by metformin treatment. Also, protein expressions of Rab4, GLUT4, and hexokinase II were unaltered after treatment. The acute metformin treatment did not affect glucose uptake in muscle of either of the genotypes. In conclusion, we provide novel evidence for a role of AMPK in potentiating the effect of insulin on glucose uptake in soleus muscle in response to chronic metformin treatment.

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Furosemide decreases the sensitivity of glucose transport to insulin in skeletal muscle in vitro

Acta Endocrinologica ◽

10.1530/eje.0.1390118 ◽

1998 ◽

Vol 139 (1) ◽

pp. 118-122 ◽

Cited By ~ 3

Author(s):

G Dimitriadis ◽

B Leighton ◽

M Parry-Billings ◽

C Tountas ◽

S Raptis ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Transport ◽

Soleus Muscle ◽

Transport Process ◽

Glucose Utilization ◽

Glucose Disposal ◽

Rat Soleus Muscle ◽

Lactate Formation

The effects of the diuretic furosemide on the sensitivity of glucose disposal to insulin were investigated in rat soleus muscle in vitro. At basal levels of insulin, the rates of 3-O-methylglucose transport, 2-deoxyglucose phosphorylation and lactate formation were not affected significantly by furosemide (0.5 mmol/l). However, furosemide significantly decreased these rates at physiological and maximal levels of insulin. The contents of 2-deoxyglucose and glucose 6-phosphate in the presence of furosemide were not significantly different from those in control muscles at all levels of insulin studied. It is concluded that furosemide decreases the sensitivity of glucose utilization to insulin in skeletal muscle by directly inhibiting the glucose transport process.

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Signalling pathways of an insulin-mimetic phosphoinositolglycan–peptide in muscle and adipose tissue

Biochemical Journal ◽

10.1042/bj3300277 ◽

1998 ◽

Vol 330 (1) ◽

pp. 277-286 ◽

Cited By ~ 32

Author(s):

Alexandra KESSLER ◽

Günter MÜLLER ◽

Susanne WIED ◽

Anna CRECELIUS ◽

Jürgen ECKEL

Keyword(s):

Adipose Tissue ◽

Insulin Receptor ◽

Tyrosine Phosphorylation ◽

Glucose Transport ◽

Insulin Action ◽

Kinase Activity ◽

Signalling Pathways ◽

Insulin Mimetic ◽

Isolated Adipocytes ◽

Stimulation Of

A novel phosphoinositolglycan-peptide (PIG-P) from the yeast Saccharomyces cerevisiae potently mimicks insulin action on glucose transport and metabolism in rat muscle and adipose tissue. The aim of the present study was to elucidate the cellular signalling pathways of this insulin-mimetic compound. Rapid onset and reversibility of PIG-P action on glucose transport were observed in isolated adipocytes with a half-time of transport stimulation of 6-8 min (insulin less than 5 min). Combined treatment with PIG-P and insulin indicated additive stimulation of glucose transport at submaximal concentrations and non-additive action of both agents at maximal doses. The tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) was markedly increased in response to PIG-P in rat cardiomyocytes without any effect on the tyrosine phosphorylation of the insulin receptor β-subunit. PIG-P action in these cells was accompanied by phosphorylation/dephosphorylation of several proteins with molecular masses of 15-30 kDa, a response not detected with insulin. Downstream signalling of IRS-1 was then analysed by monitoring IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity in cardiomyocytes. A stable (2 and 15 min incubation with PIG-P) 7-fold stimulation corresponding to about 50% of insulin action could be detected. Increased tyrosine phosphorylation of IRS-1 and enhanced PI 3-kinase activity in response to PIG-P independent of the insulin receptor was also observed in isolated adipocytes. Involvement of PI 3-kinase in PIG-P action was subsequently confirmed by the dose-dependent inhibition of PIG-P-activated glucose transport in rat diaphragm and adipocytes by the PI 3-kinase inhibitors wortmannin and LY294002. These data suggest divergent upstream signalling by insulin and PIG-P involving phosphoproteins not affected by insulin. However, PIG-P and insulin action converge at the level of IRS-1 inducing insulin-independent PI 3-kinase-mediated signalling to glucose transport.

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