Acute exercise alters skeletal muscle mitochondrial respiration and H2O2 emission in response to hyperinsulinemic-euglycemic clamp in middle-aged obese men

Background: phosphorylation of AS160 and TBC1D1 plays an important role for GLUT4 mobilization to the cell surface. The phosphorylation of AS160 and TBC1D1 in humans in response to acute exercise is not fully characterized. Objective: to study AS160 and TBC1D1 phosphorylation in human skeletal muscle after aerobic exercise followed by a hyperinsulinemic euglycemic clamp. Design: eight healthy men were studied on two occasions: 1) in the resting state and 2) in the hours after a 1-h bout of ergometer cycling. A hyperinsulinemic euglycemic clamp was initiated 240 min after exercise and in a time-matched nonexercised control condition. We obtained muscle biopsies 30 min after exercise and in a time-matched nonexercised control condition ( t = 30) and after 30 min of insulin stimulation ( t = 270) and investigated site-specific phosphorylation of AS160 and TBC1D1. Results: phosphorylation on AS160 and TBC1D1 was increased 30 min after the exercise bout, whereas phosphorylation of the putative upstream kinases, Akt and AMPK, was unchanged compared with resting control condition. Exercise augmented insulin-stimulated phosphorylation on AS160 at Ser341and Ser704270 min after exercise. No additional exercise effects were observed on insulin-stimulated phosphorylation of Thr642and Ser588on AS160 or Ser237and Thr596on TBC1D1. Conclusions: AS160 and TBC1D1 phosphorylations were evident 30 min after exercise without simultaneously increased Akt and AMPK phosphorylation. Unlike TBC1D1, insulin-stimulated site-specific AS160 phosphorylation is modified by prior exercise, but these sites do not include Thr642and Ser588. Together, these data provide new insights into phosphorylation of key regulators of glucose transport in human skeletal muscle.

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Gender differences in insulin action after a single bout of exercise

Journal of Applied Physiology ◽

10.1152/japplphysiol.00186.2004 ◽

2004 ◽

Vol 97 (3) ◽

pp. 1013-1021 ◽

Cited By ~ 15

Author(s):

Leigh Perreault ◽

Jennifer M. Lavely ◽

Bryan C. Bergman ◽

Tracy J. Horton

Keyword(s):

Gender Differences ◽

Insulin Action ◽

Acute Exercise ◽

Exercise Bout ◽

Whole Body ◽

Peripheral Tissues ◽

Euglycemic Clamp ◽

Hyperinsulinemic Euglycemic Clamp ◽

Lower Glucose ◽

Single Bout

Effects of a single exercise bout on insulin action were compared in men ( n = 10) and women ( n = 10). On an exercise day, subjects cycled for 90 min at 85% lactate threshold, whereas on a rest (control) day, they remained semirecumbent. The period of exercise, or rest, was followed by a 3-h hyperinsulinemic-euglycemic clamp (30 mU·m−2·min−1) and indirect calorimetry. Glucose kinetics were measured isotopically by using an infusion of [6,6-2H2]glucose. Glucose infusion rate (GIR) during the clamp on the rest day was not different between the genders. However, GIR on the exercise day was significantly lower in men compared with women ( P = 0.01). This was mainly due to a significantly lower glucose rate of disappearance in men compared with women ( P = 0.05), whereas no differences were observed in the endogenous glucose rate of appearance. Nonprotein respiratory quotient (NPRQ) increased significantly during the clamp from preclamp measurements in men and women on the rest day ( P < 0.01). Exercise abolished the increase in NPRQ seen during the clamp on the rest day and tended to decrease NPRQ in men. Our results indicate the following: 1) exercise abolishes the usual increase in NPRQ observed during a hyperinsulinemic-euglycemic clamp in both genders, 2) men exhibit relatively lower whole body insulin action in the 3–4 h after exercise compared with women, and 3) gender differences in insulin action may be explained by a lower glucose rate of disappearance in the men after acute exercise. Together, these data imply gender differences in insulin action postexercise exist in peripheral tissues and not in liver.

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Skeletal muscle glycogen synthase subcellular localization: effects of insulin and PPAR-α agonist (K-111) administration in rhesus monkeys

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00692.2004 ◽

2005 ◽

Vol 288 (6) ◽

pp. R1509-R1517 ◽

Cited By ~ 5

Author(s):

Heidi K. Ortmeyer ◽

Yohannes Adall ◽

Karina R. Marciani ◽

Andreas Katsiaras ◽

Alice S. Ryan ◽

...

Keyword(s):

Skeletal Muscle ◽

Subcellular Localization ◽

Protein Expression ◽

Glycogen Content ◽

Glycogen Synthase ◽

Cytosolic Fraction ◽

Peroxisome Proliferator ◽

Euglycemic Clamp ◽

Hyperinsulinemic Euglycemic Clamp ◽

Gst Activity

Insulin covalently and allosterically regulates glycogen synthase (GS) and may also cause the translocation of GS from glycogen-poor to glycogen-rich locations. We examined the possible role of subcellular localization of GS and glycogen in insulin activation of GS in skeletal muscle of six obese monkeys and determined whether 1) insulin stimulation during a hyperinsulinemic euglycemic clamp and/or peroxisome proliferator-activated receptor (PPAR)-α agonist treatment (K-111, 3 mg·kg−1·day−1; Kowa) induced translocation of GS and 2) translocation of GS was associated with insulin activation of GS. GS and glycogen were present in all fractions obtained by differential centrifugation, except for the cytosolic fraction, under both basal and insulin-stimulated conditions. We found no evidence for translocation of GS by insulin. GS total (GST) activity was strongly associated with glycogen content ( r = 0.70, P < 0.001). Six weeks of treatment with K-111 increased GST activity in all fractions, except the cytosolic fraction, and mean GST activity, GS independent activity, and glycogen content were significantly higher in the insulin-stimulated samples compared with basal samples, effects not seen with vehicle. The increase in GST activity was strongly related to the increase in glycogen content during the hyperinsulinemic euglycemic clamp after K-111 administration ( r = 0.74, P < 0.001). Neither GS protein expression nor GS gene expression was affected by insulin or by K-111 treatment. We conclude that 1) in vivo insulin does not cause translocation of GS from a glycogen-poor to a glycogen-rich location in primate skeletal muscle and 2) the mechanism of action of K-111 to improve insulin sensitivity includes an increase in GST activity without an increase in GS gene or protein expression.

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Clinical pharmacology of insulin aspart: Hyperinsulinemic euglycemic clamp study of the biosimilar product

Endocrine Abstracts ◽

10.1530/endoabs.70.aep366 ◽

2020 ◽

Author(s):

Artem Dorotenko ◽

Igor Makarenko ◽

Anna Mosikyan ◽

Maksim Magruk ◽

Roman Drai

Keyword(s):

Clinical Pharmacology ◽

Insulin Aspart ◽

Biosimilar Product ◽

Euglycemic Clamp ◽

Hyperinsulinemic Euglycemic Clamp ◽

Clamp Study

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Effects of Resistance Exercise Training and Fermented Soybean Treatment on Activity of mTOR and FoxO in Skeletal Muscle of Middle Aged Obese Rats

Korean Journal of Sport Studies ◽

10.23949/kjpe.2017.11.56.6.36 ◽

2017 ◽

Vol 56 (6) ◽

pp. 509-518 ◽

Cited By ~ 1

Author(s):

Su Ryun Jung ◽

Ki Jin Kim

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Resistance Exercise ◽

Middle Aged ◽

Resistance Exercise Training ◽

Fermented Soybean ◽

Obese Rats

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Faculty Opinions recommendation of Skeletal Muscle Fiber Type-selective Effects of Acute Exercise on Insulin-stimulated Glucose Uptake in Insulin Resistant, High Fat-fed Rats.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.735081796.793558398 ◽

2019 ◽

Author(s):

Joseph A Houmard ◽

Alec Chaves

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Muscle Fiber ◽

Acute Exercise ◽

Fiber Type ◽

Skeletal Muscle Fiber ◽

Muscle Fiber Type ◽

High Fat ◽

Insulin Resistant ◽

Selective Effects

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Curcumin induces mitochondrial biogenesis by increasing cAMP levels via PDE4A inhibition in skeletal muscle

British Journal Of Nutrition ◽

10.1017/s0007114521000490 ◽

2021 ◽

pp. 1-34

Author(s):

Hamidie Ronald D Ray ◽

Tsubasa Shibaguchi ◽

Tatsuya Yamada ◽

Rikuhide Koma ◽

Rie Ishizawa ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Expression ◽

Mitochondrial Biogenesis ◽

Mitochondrial Respiration ◽

Citrate Synthase ◽

Signalling Pathway ◽

Curcumin Treatment ◽

Camp Content ◽

Signalling Molecules ◽

Camp Levels

Abstract Background: Previous research has suggested that curcumin potentially induces mitochondrial biogenesis in skeletal muscle via increasing cAMP levels. However, the regulatory mechanisms for this phenomenon remain unknown. The purpose of the present study was to clarify the mechanism by which curcumin activates cAMP-related signalling pathways that upregulate mitochondrial biogenesis and respiration in skeletal muscle. Methods: The effect of curcumin treatment (i.p., 100 mg/kg-BW/day for 28 days) on mitochondrial biogenesis was determined in rats. The effects of curcumin and exercise (swimming for 2 h/day for 3 days) on the cAMP signalling pathway were determined in the absence and presence of phosphodiesterase (PDE) or protein kinase A (PKA) inhibitors. Mitochondrial respiration, citrate synthase (CS) activity, cAMP content, and protein expression of cAMP/PKA signalling molecules were analysed. Results: Curcumin administration increased COX-IV protein expression, and CS and complex I activity, consistent with the induction of mitochondrial biogenesis by curcumin. Mitochondrial respiration was not altered by curcumin treatment. Curcumin and PDE inhibition tended to increase cAMP levels with or without exercise. In addition, exercise increased the phosphorylation of PDE4A, whereas curcumin treatment strongly inhibited PDE4A phosphorylation regardless of exercise. Furthermore, curcumin promoted AMPK phosphorylation and PGC-1α deacetylation. Inhibition of PKA abolished the phosphorylation of AMPK. Conclusion: The present results suggest that curcumin increases cAMP levels via inhibition of PDE4A phosphorylation, which induces mitochondrial biogenesis through a cAMP/PKA/AMPK signalling pathway. Our data also suggest the possibility that curcumin utilizes a regulatory mechanism for mitochondrial biogenesis that is distinct from the exercise-induced mechanism in skeletal muscle.

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Exercise training prevents maturation-induced decrease in insulin sensitivity

Journal of Applied Physiology ◽

10.1152/jappl.1996.80.6.1963 ◽

1996 ◽

Vol 80 (6) ◽

pp. 1963-1967 ◽

Cited By ~ 16

Author(s):

N. Nakai ◽

Y. Shimomura ◽

N. Ohsaki ◽

J. Sato ◽

Y. Oshida ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Exercise Training ◽

Infusion Rate ◽

Glucose Transporter ◽

Euglycemic Clamp ◽

Glut 4 ◽

Hindlimb Muscle ◽

Female Wistar Rats ◽

Sensitivity Improvement

We examined the effects of exercise training initiated before maturation or after maturation on insulin sensitivity and glucose transporter GLUT-4 content in membrane fractions of skeletal muscle. Female Wistar rats (4 wk of age) were divided into sedentary and exercise-trained groups. At 12 wk of age, a subset of the trained animals (Tr) was killed along with a subset of sedentary controls (Sed). One-half of the remaining sedentary animals remained sedentary (Sed-Sed) while the other half began exercise training (Sed-Tr). The remaining rats in the original trained group continued to train (Tr-Tr). Euglycemic clamp (insulin infusion rate at 6 mU.kg body wt-1. min-1) was performed at 4, 12, and 27 wk. After euglycemic clamp in all animals except the 4-wk-old, hindlimb (gastrocnemius and part of quadriceps) muscles were removed for preparation of membrane fractions. In sedentary rats, glucose infusion rate (GIR) during euglycemic clamp was decreased from 15.9 mg.kg-1.min-1 at 4 wk of age to 9.8 mg.kg-1.min-1 at 12 wk of age and 9.1 mg.kg-1.min-1 at 27 wk of age. In exercise-trained rats, the GIR was not significantly decreased by maturation (at 12 wk) and further aging (at 27 wk). Initiation of exercise after maturation restored the GIR at 27 wk of age to the same levels as these for the corresponding exercise-trained rats. GLUT-4 content in plasma and intracellular membrane fractions of hindlimb muscle obtained just after euglycemic clamp showed the same trend as the results of GIR. These results suggest that exercise training prevented the maturation-induced decrease in insulin sensitivity. Improvement of insulin sensitivity caused by exercise training was attributed, at least in part, to the increase in insulin-sensitive GLUT-4 on the plasma membrane in skeletal muscle.

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Does impaired mitochondrial function affect insulin signaling and action in cultured human skeletal muscle cells?

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00267.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. E97-E102 ◽

Cited By ~ 8

Author(s):

Audrey E. Brown ◽

Matthias Elstner ◽

Stephen J. Yeaman ◽

Douglass M. Turnbull ◽

Mark Walker

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Insulin Signaling ◽

Mitochondrial Respiration ◽

Respiratory Function ◽

Insulin Action ◽

Human Skeletal Muscle ◽

Human Skeletal Muscle Cells ◽

Basal Glucose Uptake

Insulin-resistant type 2 diabetic patients have been reported to have impaired skeletal muscle mitochondrial respiratory function. A key question is whether decreased mitochondrial respiration contributes directly to the decreased insulin action. To address this, a model of impaired cellular respiratory function was established by incubating human skeletal muscle cell cultures with the mitochondrial inhibitor sodium azide and examining the effects on insulin action. Incubation of human skeletal muscle cells with 50 and 75 μM azide resulted in 48 ± 3% and 56 ± 1% decreases, respectively, in respiration compared with untreated cells mimicking the level of impairment seen in type 2 diabetes. Under conditions of decreased respiratory chain function, insulin-independent (basal) glucose uptake was significantly increased. Basal glucose uptake was 325 ± 39 pmol/min/mg (mean ± SE) in untreated cells. This increased to 669 ± 69 and 823 ± 83 pmol/min/mg in cells treated with 50 and 75 μM azide, respectively (vs. untreated, both P < 0.0001). Azide treatment was also accompanied by an increase in basal glycogen synthesis and phosphorylation of AMP-activated protein kinase. However, there was no decrease in glucose uptake following insulin exposure, and insulin-stimulated phosphorylation of Akt was normal under these conditions. GLUT1 mRNA expression remained unchanged, whereas GLUT4 mRNA expression increased following azide treatment. In conclusion, under conditions of impaired mitochondrial respiration there was no evidence of impaired insulin signaling or glucose uptake following insulin exposure in this model system.

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