Overexpression or ablation of JNK in skeletal muscle has no effect on glycogen synthase activity

2004 ◽  
Vol 287 (1) ◽  
pp. C200-C208 ◽  
Author(s):  
Nobuharu Fujii ◽  
Marni D. Boppart ◽  
Scott D. Dufresne ◽  
Patricia F. Crowley ◽  
Alison C. Jozsi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Contraction ◽  
Glycogen Synthase ◽  
Contractile Activity ◽  
S6 Kinase ◽  
Jnk Signaling ◽  
Phosphorylation State ◽  
Mouse Skeletal Muscle ◽  
Major Mechanism ◽  
Glycogen Synthase Activity

c-Jun NH2-terminal kinase (JNK) is highly expressed in skeletal muscle and is robustly activated in response to muscle contraction. Little is known about the biological functions of JNK signaling in terminally differentiated muscle cells, although this protein has been proposed to regulate insulin-stimulated glycogen synthase activity in mouse skeletal muscle. To determine whether JNK signaling regulates contraction-stimulated glycogen synthase activation, we applied an electroporation technique to induce JNK overexpression (O/E) in mouse skeletal muscle. Ten days after electroporation, in situ muscle contraction increased JNK activity 2.6-fold in control muscles and 15-fold in the JNK O/E muscles. Despite the enormous activation of JNK activity in JNK O/E muscles, contraction resulted in similar increases in glycogen synthase activity in control and JNK O/E muscles. Consistent with these findings, basal and contraction-induced glycogen synthase activity was normal in muscles of both JNK1- and JNK2-deficient mice. JNK overexpression in muscle resulted in significant alterations in the basal phosphorylation state of several signaling proteins, such as extracellular signal-regulated kinase 1/2, p90 S6 kinase, glycogen synthase kinase 3, protein kinase B/Akt, and p70 S6 kinase, in the absence of changes in the expression of these proteins. These data suggest that JNK signaling regulates the phosphorylation state of several kinases in skeletal muscle. JNK activation is unlikely to be the major mechanism by which contractile activity increases glycogen synthase activity in skeletal muscle.

scholarly journals Altered Extracellular Signal-Regulated Kinase Signaling and Glycogen Metabolism in Skeletal Muscle from p90 Ribosomal S6 Kinase 2 Knockout Mice

2001 ◽  
Vol 21 (1) ◽  
pp. 81-87 ◽  
Author(s):  
Scott D. Dufresne ◽  
Christian Bjørbæk ◽  
Karim El-Haschimi ◽  
Yi Zhao ◽  
William G. Aschenbach ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Knockout Mice ◽  
Muscle Glycogen ◽  
Glycogen Synthase ◽  
S6 Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
P90 Ribosomal S6 Kinase ◽  
Ribosomal S6 Kinase ◽  
Glycogen Synthase Activity

ABSTRACT The p90 ribosomal S6 kinase (RSK), a cytosolic substrate for the extracellular signal-regulated kinase (ERK), is involved in transcriptional regulation, and one isoform (RSK2) has been implicated in the activation of glycogen synthase by insulin. To determine RSK2 function in vivo, mice lacking a functional rsk2 gene were generated and studied in response to insulin and exercise, two potent stimulators of the ERK cascade in skeletal muscle. RSK2 knockout (KO) mice weigh 10% less and are 14% shorter than wild-type (WT) mice. They also have impaired learning and coordination. Hindlimb skeletal muscles were obtained from mice 10, 15, or 30 min after insulin injection or immediately after strenuous treadmill exercise for 60 min. While insulin and exercise significantly increased ERK phosphorylation in skeletal muscle from both WT and KO mice, the increases were twofold greater in the KO animals. This occurred despite 27% lower ERK2 protein expression in skeletal muscle of KO mice. KO mice had 18% less muscle glycogen in the fasted basal state, and insulin increased glycogen synthase activity more in KO than WT mice. The enhanced insulin-stimulated increases in ERK and glycogen synthase activities in KO mice were not associated with higher insulin receptor or with IRS1 tyrosine phosphorylation or with IRS1 binding to phosphatidylinositol 3-kinase. However, insulin-stimulated serine phosphorylation of Akt was significantly higher in the KO animals. c-fos mRNA was increased similarly in muscle from WT and KO mice in response to insulin (2.5-fold) and exercise (15-fold). In conclusion, RSK2 likely plays a major role in feedback inhibition of the ERK pathway in skeletal muscle. Furthermore, RSK2 is not required for activation of muscle glycogen synthase by insulin but may indirectly modulate muscle glycogen synthase activity and/or glycogen content by other mechanisms, possibly through regulation of Akt. RSK2 knockout mice may be a good animal model for the study of Coffin-Lowry syndrome.

Increased concentrations of glycogen synthase protein in skeletal muscle of patients with NIDDM

1995 ◽  
Vol 269 (1) ◽  
pp. E27-E32 ◽  
Author(s):  
M. Lofman ◽  
H. Yki-Jarvinen ◽  
M. Parkkonen ◽  
J. Lindstrom ◽  
L. Koranyi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Protein Concentration ◽  
Glycogen Synthase ◽  
Glycogen Metabolism ◽  
Dependent Diabetes Mellitus ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Control Subjects ◽  
Significant Difference ◽  
Glycogen Synthase Activity

To examine whether changes in the glycogen synthase protein concentration contribute to impaired insulin-stimulated glycogen metabolism in patients with noninsulin-dependent diabetes mellitus (NIDDM), muscle biopsies were taken before and after a 4-h euglycemic hyperinsulinemic clamp to measure glycogen synthase activity and glycogen synthase protein concentrations in 14 patients with NIDDM and in 17 control subjects. Nonoxidative glucose metabolism was reduced by 64% in patients with NIDDM compared with control subjects and correlated with insulin-stimulated glycogen synthase activity (r = 0.55, P < 0.05). The concentration of glycogen synthase protein in skeletal muscle was higher in patients with NIDDM than in control subjects (6.75 +/- 0.88 vs. 4.41 +/- 0.50 counts.min-1.micrograms protein-1, P < 0.05), whereas there was no significant difference in glycogen synthase mRNA concentration between the two groups. The glycogen synthase protein concentration correlated inversely with the rate of nonoxidative glucose metabolism (r = -0.63, P < 0.05). These findings indicate that the amount of glycogen synthase protein is increased in skeletal muscle of patients with NIDDM. The increase in the glycogen synthase protein may serve to compensate for a functional defect in the activation of the enzyme by insulin.

scholarly journals Influence of Exercise Training on Skeletal Muscle Insulin Resistance in Aging: Spotlight on Muscle Ceramides

2020 ◽  
Vol 21 (4) ◽  
pp. 1514 ◽  
Author(s):  
Paul T. Reidy ◽  
Ziad S. Mahmassani ◽  
Alec I. McKenzie ◽  
Jonathan J. Petrocelli ◽  
Scott A. Summers ◽  
...  
Keyword(s):  
Physical Activity ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Muscle Contraction ◽  
Contractile Activity ◽  
Skeletal Muscle Insulin Resistance ◽  
Ceramide Content ◽  
Subcellular Compartmentalization ◽  
Skeletal Muscle Insulin Sensitivity

Intramuscular lipid accumulation has been associated with insulin resistance (IR), aging, diabetes, dyslipidemia, and obesity. A substantial body of evidence has implicated ceramides, a sphingolipid intermediate, as potent antagonists of insulin action that drive insulin resistance. Indeed, genetic mouse studies that lower ceramides are potently insulin sensitizing. Surprisingly less is known about how physical activity (skeletal muscle contraction) regulates ceramides, especially in light that muscle contraction regulates insulin sensitivity. The purpose of this review is to critically evaluate studies (rodent and human) concerning the relationship between skeletal muscle ceramides and IR in response to increased physical activity. Our review of the literature indicates that chronic exercise reduces ceramide levels in individuals with obesity, diabetes, or hyperlipidemia. However, metabolically healthy individuals engaged in increased physical activity can improve insulin sensitivity independent of changes in skeletal muscle ceramide content. Herein we discuss these studies and provide context regarding the technical limitations (e.g., difficulty assessing the myriad ceramide species, the challenge of obtaining information on subcellular compartmentalization, and the paucity of flux measurements) and a lack of mechanistic studies that prevent a more sophisticated assessment of the ceramide pathway during increased contractile activity that lead to divergences in skeletal muscle insulin sensitivity.

Fasting and diabetes alter adipose tissue glycogen synthase

1984 ◽  
Vol 247 (5) ◽  
pp. E581-E584
Author(s):  
H. R. Kaslow ◽  
R. D. Eichner
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Enzyme Purification ◽  
Glycogen Synthase ◽  
Streptozotocin Diabetes ◽  
Positive Cooperativity ◽  
Maximal Activation ◽  
Glucose Incorporation ◽  
Glycogen Synthase Activity

In a previous report (J. Biol. Chem. 254: 4678-4683, 1979), we showed that fasting blunted the ability of insulin to promote glucose incorporation into glycogen in vitro. In addition, we showed that glycogen synthase activity was altered in two ways: the concentration of glucose 6-P causing half-maximal activation increased, and positive cooperativity appeared in the glucose 6-P activation of the enzyme. We now show that streptozotocin-diabetes causes the same changes in glucose incorporation and glycogen synthase activity. We show that these changes in glycogen synthase activity persist during enzyme purification; thus it is likely the changes are a result of a structural alteration of the enzyme. Because glycogenolysis of a glycogen particle from rabbit skeletal muscle also caused the appearance of positive cooperativity, we propose that both phosphorylation and glycogenolysis are involved in the appearance of positive cooperativity.

Modulation of muscle insulin resistance by selective inhibition of GSK-3 in Zucker diabetic fatty rats

2003 ◽  
Vol 284 (5) ◽  
pp. E892-E900 ◽  
Author(s):  
Erik J. Henriksen ◽  
Tyson R. Kinnick ◽  
Mary K. Teachey ◽  
Matthew P. O'Keefe ◽  
David Ring ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Transport ◽  
Glycogen Synthase ◽  
Oral Glucose ◽  
Type I ◽  
Insulin Resistant ◽  
Zucker Diabetic Fatty Rats ◽  
Zdf Rats ◽  
Glycogen Synthase Activity

A role for elevated glycogen synthase kinase-3 (GSK-3) activity in the multifactorial etiology of insulin resistance is now emerging. However, the utility of specific GSK-3 inhibition in modulating insulin resistance of skeletal muscle glucose transport is not yet fully understood. Therefore, we assessed the effects of novel, selective organic inhibitors of GSK-3 (CT-98014 and CT-98023) on glucose transport in insulin-resistant muscles of Zucker diabetic fatty (ZDF) rats. Incubation of type IIb epitrochlearis and type I soleus muscles from ZDF rats with CT-98014 increased glycogen synthase activity (49 and 50%, respectively, P < 0.05) but did not alter basal glucose transport (2-deoxyglucose uptake). In contrast, CT-98014 significantly increased the stimulatory effects of both submaximal and maximal insulin concentrations in epitrochlearis (37 and 24%) and soleus (43 and 26%), and these effects were associated with increased cell-surface GLUT4 protein. Lithium enhanced glycogen synthase activity and both basal and insulin-stimulated glucose transport in muscles from ZDF rats. Acute oral administration (2 × 30 mg/kg) of CT-98023 to ZDF rats caused elevations in GSK-3 inhibitor concentrations in plasma and muscle. The glucose and insulin responses during a subsequent oral glucose tolerance test were reduced by 26 and 34%, respectively, in the GSK-3 inhibitor-treated animals. Thirty minutes after the final GSK-3 inhibitor treatment, insulin-stimulated glucose transport was significantly enhanced in epitrochlearis (57%) and soleus (43%). Two hours after the final treatment, insulin-mediated glucose transport was still significantly elevated (26%) only in the soleus. These results indicate that specific inhibition of GSK-3 enhances insulin action on glucose transport in skeletal muscle of the insulin-resistant ZDF rat. This unique approach may hold promise as a pharmacological treatment against insulin resistance of skeletal muscle glucose disposal.

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