Exercise-Induced Transient Increase in IL-6 Stimulates GLUT4 Expression and Enhances Insulin Sensitivity in Mouse Skeletal Muscle

Glucose uptake and homeostasis are regulated mainly by skeletal muscle (SM), white adipose tissue (WAT), pancreas, and the liver. Participation of estradiol in this regulation is still under intense investigation. We have demonstrated that, in SM of male mice, expression of the insulin-regulated glucose transporter (GLUT)4 is reduced by estrogen receptor (ER)β agonists. In the present study, to investigate the relative contributions of ERα and ERβ in glucose homeostasis, we examined the effects of tamoxifen (Tam) on GLUT4 expression in SM and WAT in wild-type (WT) and ER−/− mice. ERβ−/− mice were characterized by fasting hypoglycemia, increased levels of SM GLUT4, pancreatic islet hypertrophy, and a belated rise in plasma insulin in response to a glucose challenge. ERα−/− mice, on the contrary, were hyperglycemic and glucose intolerant, and expression of SM GLUT4 was markedly lower than in WT mice. Tam had no effect on glucose tolerance or insulin sensitivity in WT mice. In ERα−/− mice, Tam increased GLUT4 and improved insulin sensitivity. i.e., it behaved as an ERβ antagonist in SM but had no effect on WAT. In ERβ−/− mice, Tam did not affect GLUT4 in SM but acted as an ERα antagonist in WAT, decreasing GLUT4. Thus, in the interplay between ERα and ERβ, ERβ-mediated repression of GLUT4 predominates in SM but ERα-mediated induction of GLUT4 predominates in WAT. This tissue-specific difference in dominance of one ER over the other is reflected in the ratio of the expression of the two receptors. ERα predominates in WAT and ERβ in SM.

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The off rate of Ca2+ from troponin C is regulated by force-generating cross bridges in skeletal muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.00376.2001 ◽

2002 ◽

Vol 92 (6) ◽

pp. 2409-2418 ◽

Cited By ~ 29

Author(s):

Ying Wang ◽

W. Glenn L. Kerrick

Keyword(s):

Skeletal Muscle ◽

Troponin C ◽

Transient Increase ◽

Skinned Fibers ◽

Mouse Skeletal Muscle ◽

Actomyosin Atpase ◽

Intact Muscle ◽

Intracellular Ca ◽

Cross Bridges ◽

Fenn Effect

The effects of dissociation of force-generating cross bridges on intracellular Ca2+, pCa-force, and pCa-ATPase relationships were investigated in mouse skeletal muscle. Mechanical length perturbations were used to dissociate force-generating cross bridges in either intact or skinned fibers. In intact muscle, an impulse stretch or release, a continuous length vibration, a nonoverlap stretch, or an unloaded shortening during a twitch caused a transient increase in intracellular Ca2+ compared with that in isometric controls and resulted in deactivation of the muscle. In skinned fibers, sinusoidal length vibrations shifted pCa-force and pCa-actomyosin ATPase rate relationships to higher Ca2+ concentrations and caused actomyosin ATPase rate to decrease at submaximal Ca2+ and increase at maximal Ca2+ activation. These results suggest that dissociation of force-generating cross bridges during a twitch causes the off rate of Ca2+ from troponin C to increase (a decrease in the Ca2+ affinity of troponin C), thus decreasing the Ca2+ sensitivity and resulting in the deactivation of the muscle. The results also suggest that the Fenn effect only exists at maximal but not submaximal force-activating Ca2+ concentrations.

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Reversal of enhanced muscle glucose transport after exercise: roles of insulin and glucose

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1990.259.5.e685 ◽

1990 ◽

Vol 259 (5) ◽

pp. E685-E691 ◽

Cited By ~ 22

Author(s):

E. A. Gulve ◽

G. D. Cartee ◽

J. R. Zierath ◽

V. M. Corpus ◽

J. O. Holloszy

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Glucose Transport ◽

Transport Process ◽

Sugar Transport ◽

Transport Activity ◽

High Concentration ◽

Exercise Induced ◽

Muscle Glucose Transport

Exercise stimulates insulin-independent glucose transport in skeletal muscle and also increases the sensitivity of the glucose transport process in muscle to insulin. A previous study [D. A. Young, H. Wallberg-Henriksson, M. D. Sleeper, and J. O. Holloszy. Am. J. Physiol. 253 (Endocrinol. Metab. 16): E331–E335, 1987] showed that the exercise-induced increase in glucose transport activity disappears rapidly when rat epitrochlearis muscles are incubated for 3 h in vitro in the absence of insulin and that 7.5 microU/ml insulin in the incubation medium apparently slowed the loss of enhanced sugar transport. We examined whether addition of insulin several hours after exercise increases glucose transport to the same extent as continuous insulin exposure. Addition of 7.5 microU/ml insulin 2.5 h after exercise (when glucose transport has returned to basal levels) increased sugar transport to the same level as that which resulted from continuous insulin exposure. This finding provides evidence for an increase in insulin sensitivity rather than a slowing of reversal of the exercise-induced increase in insulin-independent glucose transport activity. Glucose transport was enhanced only at submaximal, not at maximal, insulin concentrations. Exposure to a high concentration of glucose and a low insulin concentration reduced the exercise-induced increase in insulin-sensitive glucose transport. Incubation with a high concentration of 2-deoxy-D-glucose (2-DG) did not alter the increase in insulin sensitivity, even though a large amount of 2-DG entered the muscle and was phosphorylated.(ABSTRACT TRUNCATED AT 250 WORDS)

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ADAPTATION OF MOUSE SKELETAL MUSCLE TO TWO BOUTS OF EXERCISE-INDUCED INJURY

Medicine & Science in Sports & Exercise ◽

10.1097/00005768-200205001-01025 ◽

2002 ◽

Vol 34 (5) ◽

pp. S183

Author(s):

C P. Ingalls ◽

T Nofal ◽

C Papadopoulos

Keyword(s):

Skeletal Muscle ◽

Mouse Skeletal Muscle ◽

Exercise Induced

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CLOCK and BMAL1 Regulate Muscle Insulin Sensitivity via SIRT1 in Male Mice

Endocrinology ◽

10.1210/en.2015-2027 ◽

2016 ◽

Vol 157 (6) ◽

pp. 2259-2269 ◽

Cited By ~ 33

Author(s):

Jun Liu ◽

Ben Zhou ◽

Menghong Yan ◽

Rui Huang ◽

Yuangao Wang ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Molecular Mechanisms ◽

Ectopic Expression ◽

Sirtuin 1 ◽

C2c12 Myotubes ◽

Constant Darkness ◽

Circadian Misalignment ◽

Mouse Skeletal Muscle

Circadian misalignment induces insulin resistance in both human and animal models, and skeletal muscle is the largest organ response to insulin. However, how circadian clock regulates muscle insulin sensitivity and the underlying molecular mechanisms are still largely unknown. Here we show circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (BMAL)-1, two core circadian transcription factors, are down-regulated in insulin-resistant C2C12 myotubes and mouse skeletal muscle. Furthermore, insulin signaling is attenuated in the skeletal muscle of ClockΔ19/Δ19 mice, and knockdown of CLOCK or BMAL1 by small interfering RNAs induces insulin resistance in C2C12 myotubes. Consistently, ectopic expression of CLOCK and BMAL1 improves insulin sensitivity in C2C12 myotubes. Moreover, CLOCK and BMAL1 regulate the expression of sirtuin 1 (SIRT1), an important regulator of insulin sensitivity, in C2C12 myotubes and mouse skeletal muscle, and two E-box elements in Sirt1 promoter are responsible for its CLOCK- and BMAL1-dependent transcription in muscle cells. Further studies show that CLOCK and BMAL1 regulate muscle insulin sensitivity through SIRT1. In addition, we find that BMAL1 and SIRT1 are decreased in the muscle of mice maintained in constant darkness, and resveratrol supplementation activates SIRT1 and improves insulin sensitivity. All these data demonstrate that CLOCK and BMAL1 regulate muscle insulin sensitivity via SIRT1, and activation of SIRT1 might be a potential valuable strategy to attenuate muscle insulin resistance related to circadian misalignment.

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NOS isoform-specific regulation of basal but not exercise-induced mitochondrial biogenesis in mouse skeletal muscle

The Journal of Physiology ◽

10.1113/jphysiol.2007.141309 ◽

2007 ◽

Vol 585 (1) ◽

pp. 253-262 ◽

Cited By ~ 48

Author(s):

G. D. Wadley ◽

J. Choate ◽

G. K. McConell

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Biogenesis ◽

Mouse Skeletal Muscle ◽

Specific Regulation ◽

Exercise Induced

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Prior AICAR Stimulation Increases Insulin Sensitivity in Mouse Skeletal Muscle in an AMPK-Dependent Manner

Diabetes ◽

10.2337/db14-1402 ◽

2014 ◽

Vol 64 (6) ◽

pp. 2042-2055 ◽

Cited By ~ 74

Author(s):

Rasmus Kjøbsted ◽

Jonas T. Treebak ◽

Joachim Fentz ◽

Louise Lantier ◽

Benoit Viollet ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Dependent Manner ◽

Mouse Skeletal Muscle

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Effect of N-acetylcysteine infusion on exercise-induced modulation of insulin sensitivity and signaling pathways in human skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00605.2014 ◽

2015 ◽

Vol 309 (4) ◽

pp. E388-E397 ◽

Cited By ~ 25

Author(s):

Adam J. Trewin ◽

Leonidas S. Lundell ◽

Ben D. Perry ◽

Kim Vikhe Patil ◽

Alexander V. Chibalin ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Repeated Measures ◽

Insulin Action ◽

Human Skeletal Muscle ◽

Protein Signaling ◽

Insulin Stimulation ◽

Double Blind ◽

Exercise Induced ◽

Muscle Biopsies

—Reactive oxygen species (ROS) produced in skeletal muscle may play a role in potentiating the beneficial responses to exercise; however, the effects of exercise-induced ROS on insulin action and protein signaling in humans has not been fully elucidated. Seven healthy, recreationally active participants volunteered for this double-blind, randomized, repeated-measures crossover study. Exercise was undertaken with infusion of saline (CON) or the antioxidant N-acetylcysteine (NAC) to attenuate ROS. Participants performed two 1-h cycling exercise sessions 7–14 days apart, 55 min at 65% V̇o2peak plus 5 min at 85%V̇o2peak, followed 3 h later by a 2-h hyperinsulinemic euglycemic clamp (40 mIU·min−1·m2) to determine insulin sensitivity. Four muscle biopsies were taken on each trial day, at baseline before NAC infusion (BASE), after exercise (EX), after 3-h recovery (REC), and post-insulin clamp (PI). Exercise, ROS, and insulin action on protein phosphorylation were evaluated with immunoblotting. NAC tended to decrease postexercise markers of the ROS/protein carbonylation ratio by −13.5% ( P = 0.08) and increase the GSH/GSSG ratio twofold vs. CON ( P < 0.05). Insulin sensitivity was reduced (−5.9%, P < 0.05) by NAC compared with CON without decreased phosphorylation of Akt or AS160. Whereas p-mTOR was not significantly decreased by NAC after EX or REC, phosphorylation of the downstream protein synthesis target kinase p70S6K was blunted by 48% at PI with NAC compared with CON ( P < 0.05). We conclude that NAC infusion attenuated muscle ROS and postexercise insulin sensitivity independent of Akt signaling. ROS also played a role in normal p70S6K phosphorylation in response to insulin stimulation in human skeletal muscle.

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