Calorie Restriction Enhances Insulin-Stimulated Glucose Uptake and Akt Phosphorylation in Both Fast-Twitch and Slow-Twitch Skeletal Muscle of 24-Month-Old Rats

Calorie restriction [CR; ∼65% of ad libitum (AL) intake] improves insulin-stimulated glucose uptake (GU) and Akt phosphorylation in skeletal muscle. We aimed to elucidate the effects of CR on 1) processes that regulate Akt phosphorylation [insulin receptor (IR) tyrosine phosphorylation, IR substrate 1-phosphatidylinositol 3-kinase (IRS-PI3K) activity, and Akt binding to regulatory proteins (heat shock protein 90, Appl1, protein phosphatase 2A)]; 2) Akt substrate of 160-kDa (AS160) phosphorylation on key phosphorylation sites; and 3) atypical PKC (aPKC) activity. Isolated epitrochlearis (fast-twitch) and soleus (slow-twitch) muscles from AL or CR (6 mo duration) 9-mo-old male F344BN rats were incubated with 0, 1.2, or 30 nM insulin and 2-deoxy-[3H]glucose. Some CR effects were independent of insulin dose or muscle type: CR caused activation of Akt (Thr308and Ser473) and GU in both muscles at both insulin doses without CR effects on IRS1-PI3K, Akt-PP2A, or Akt-Appl1. Several muscle- and insulin dose-specific CR effects were revealed. Akt-HSP90 binding was increased in the epitrochlearis; AS160 phosphorylation (Ser588and Thr642) was greater for CR epitrochlearis at 1.2 nM insulin; and IR phosphorylation and aPKC activity were greater for CR in both muscles with 30 nM insulin. On the basis of these data, our working hypothesis for improved insulin-stimulated GU with CR is as follows: 1) elevated Akt phosphorylation is fundamental, regardless of muscle or insulin dose; 2) altered Akt binding to regulatory proteins (HSP90 and unidentified Akt partners) is involved in the effects of CR on Akt phosphorylation; 3) Akt effects on GU depend on muscle- and insulin dose-specific elevation in phosphorylation of Akt substrates, including, but not limited to, AS160; and 4) greater IR phosphorylation and aPKC activity may contribute at higher insulin doses.

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Calorie restriction leads to greater Akt2 activity and glucose uptake by insulin-stimulated skeletal muscle from old rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00449.2015 ◽

2016 ◽

Vol 310 (5) ◽

pp. R449-R458 ◽

Cited By ~ 8

Author(s):

Haiyan Wang ◽

Edward B. Arias ◽

Gregory D. Cartee

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Calorie Restriction ◽

Akt Inhibitor ◽

Muscle Insulin Resistance ◽

Skeletal Muscle Insulin Resistance ◽

Age Related ◽

Old Rats ◽

Ad Libitum ◽

New Evidence

Skeletal muscle insulin resistance is associated with many common age-related diseases, but moderate calorie restriction (CR) can substantially elevate glucose uptake by insulin-stimulated skeletal muscle from both young and old rats. The current study evaluated the isolated epitrochlearis muscle from ∼24.5-mo-old rats that were either fed ad libitum (AL) or subjected to CR (consuming ∼65% of ad libitum, AL, intake beginning at ∼22.5 mo old). Some muscles were also incubated with MK-2206, a potent and selective Akt inhibitor. The most important results were that in isolated muscles, CR vs. AL resulted in 1) greater insulin-stimulated glucose uptake 2) that was accompanied by significantly increased insulin-mediated activation of Akt2, as indicated by greater phosphorylation on both Thr309and Ser474along with greater Akt2 activity, 3) concomitant with enhanced phosphorylation of several Akt substrates, including an Akt substrate of 160 kDa on Thr642and Ser588, filamin C on Ser2213and proline-rich Akt substrate of 40 kDa on Thr246, but not TBC1D1 on Thr596; and 4) each of the CR effects was eliminated by MK-2206. These data provide compelling new evidence linking greater Akt2 activation to the CR-induced elevation of insulin-stimulated glucose uptake by muscle from old animals.

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Mechanisms for independent and combined effects of calorie restriction and acute exercise on insulin-stimulated glucose uptake by skeletal muscle of old rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00618.2014 ◽

2015 ◽

Vol 308 (7) ◽

pp. E603-E612 ◽

Cited By ~ 14

Author(s):

Naveen Sharma ◽

Haiyan Wang ◽

Edward B. Arias ◽

Carlos M. Castorena ◽

Gregory D. Cartee

Keyword(s):

Glucose Uptake ◽

Calorie Restriction ◽

Insulin Signaling ◽

Acute Exercise ◽

Exercise Group ◽

Combined Effects ◽

Additional Increase ◽

Akt Phosphorylation ◽

Akt Activation ◽

Old Rats

Either calorie restriction [CR; consuming 60–65% of ad libitum (AL) intake] or acute exercise can independently improve insulin sensitivity in old age, but their combined effects on muscle insulin signaling and glucose uptake have previously been unknown. Accordingly, we assessed the independent and combined effects of CR (beginning at 14 wk old) and acute exercise (3–4 h postexercise) on insulin signaling and glucose uptake in insulin-stimulated epitrochlearis muscles from 30-mo-old rats. Either CR alone or exercise alone vs. AL sedentary controls induced greater insulin-stimulated glucose uptake. Combined CR and exercise vs. either treatment alone caused an additional increase in insulin-stimulated glucose uptake. Either CR or exercise alone vs. AL sedentary controls increased Akt Ser473and Akt Thr308phosphorylation. Combined CR and exercise further elevated Akt phosphorylation on both sites. CR alone, but not exercise alone, vs. AL sedentary controls significantly increased Akt substrate of 160 kDa (AS160) Ser588and Thr642phosphorylation. Combined CR and exercise did not further enhance AS160 phosphorylation. Exercise alone, but not CR alone, modestly increased GLUT4 abundance. Combined CR and exercise did not further elevate GLUT4 content. These results suggest that CR or acute exercise independently increases insulin-stimulated glucose uptake via overlapping (greater Akt phosphorylation) and distinct (greater AS160 phosphorylation for CR, greater GLUT4 for exercise) mechanisms. Our working hypothesis is that greater insulin-stimulated glucose uptake in the combined CR and exercise group vs. CR or exercise alone relies on greater Akt activation, leading to greater phosphorylation of one or more Akt substrates other than AS160.

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A persistent increase in insulin-stimulated glucose uptake by both fast-twitch and slow-twitch skeletal muscles after a single exercise session by old rats

AGE ◽

10.1007/s11357-012-9383-0 ◽

2012 ◽

Vol 35 (3) ◽

pp. 573-582 ◽

Cited By ~ 17

Author(s):

Yuanyuan Xiao ◽

Naveen Sharma ◽

Edward B. Arias ◽

Carlos M. Castorena ◽

Gregory D. Cartee

Keyword(s):

Glucose Uptake ◽

Skeletal Muscles ◽

Exercise Session ◽

Old Rats ◽

Slow Twitch ◽

Fast Twitch

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Effects of Acute Exercise Combined With Calorie Restriction Initiated Late-in-Life on Insulin Signaling, Lipids, and Glucose Uptake in Skeletal Muscle From Old Rats

The Journals of Gerontology Series A ◽

10.1093/gerona/gly222 ◽

2018 ◽

Vol 75 (2) ◽

pp. 207-217

Author(s):

Kentaro Oki ◽

Edward B Arias ◽

Makoto Kanzaki ◽

Gregory D Cartee

Keyword(s):

Mass Spectrometry ◽

Skeletal Muscle ◽

Glucose Uptake ◽

Calorie Restriction ◽

Insulin Signaling ◽

Acute Exercise ◽

Signaling Proteins ◽

Post Exercise ◽

Old Rats ◽

Ad Libitum

Abstract We evaluated effects of calorie restriction (CR: consuming 60–65% of ad libitum [AL] intake) initiated late-in-life with or without acute exercise on insulin-stimulated glucose uptake (ISGU) of skeletal muscle by studying four groups of 26-month-old rats: sedentary-AL, sedentary-CR (8-week duration), 3 hours post-exercise (3hPEX)-AL and 3hPEX-CR. ISGU was determined in isolated epitrochlearis muscles incubated ± insulin. Muscles were assessed for signaling proteins (immunoblotting) and lipids (mass spectrometry). ISGU from sedentary-CR and 3hPEX-AL exceeded sedentary-AL; 3hPEX-CR exceeded all other groups. Akt (Ser473, Thr308) and Akt substrate of 160 kDa (AS160; Ser588, Thr642, Ser704) phosphorylation levels tracked with ISGU. Among the 477 lipids detected, 114 were altered by CR (including reductions in 15 of 25 acylcarnitines), and 27 were altered by exercise (including reductions in 18 of 22 lysophosphatidylcholines) with only six lipids overlapping between CR and exercise. ISGU significantly correlated with 23 lipids, including: acylcarnitine 20:1 (r = .683), lysophosphatidylethanolamine19:0 (r = −.662), acylcarnitine 24:0 (r = .611), and plasmenyl-phosphatidylethanolamine 37:5 (r = −.603). Muscle levels of ceramides (a lipid class previously linked to insulin resistance) were not altered by CR and/or exercise nor significantly correlated with ISGU, implicating other mechanisms (which potentially involve other lipids identified in this study) for greater ISGU and Akt and AS160 phosphorylation with these interventions.

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Insulin Signaling and Glucose Uptake in the Soleus Muscle of 30-Month-Old Rats After Calorie Restriction With or Without Acute Exercise

The Journals of Gerontology Series A ◽

10.1093/gerona/glv142 ◽

2015 ◽

Vol 71 (3) ◽

pp. 323-332 ◽

Cited By ~ 10

Author(s):

Haiyan Wang ◽

Naveen Sharma ◽

Edward B. Arias ◽

Gregory D. Cartee

Keyword(s):

Glucose Uptake ◽

Calorie Restriction ◽

Soleus Muscle ◽

Insulin Signaling ◽

Acute Exercise ◽

Old Rats

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NF-κB-Inducing Kinase (NIK) Mediates Skeletal Muscle Insulin Resistance: Blockade by Adiponectin

Endocrinology ◽

10.1210/en.2011-1343 ◽

2011 ◽

Vol 152 (10) ◽

pp. 3622-3627 ◽

Cited By ~ 26

Author(s):

Sanjeev Choudhary ◽

Sandeep Sinha ◽

Yanhua Zhao ◽

Srijita Banerjee ◽

Padma Sathyanarayana ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Uptake ◽

Kinase Activity ◽

Pi3 Kinase ◽

Dominant Negative ◽

Muscle Insulin Resistance ◽

Akt Phosphorylation ◽

Skeletal Muscle Insulin Resistance ◽

Obese Subjects

Enhanced levels of nuclear factor (NF)-κB-inducing kinase (NIK), an upstream kinase in the NF-κB pathway, have been implicated in the pathogenesis of chronic inflammation in diabetes. We investigated whether increased levels of NIK could induce skeletal muscle insulin resistance. Six obese subjects with metabolic syndrome underwent skeletal muscle biopsies before and six months after gastric bypass surgery to quantitate NIK protein levels. L6 skeletal myotubes, transfected with NIK wild-type or NIK kinase-dead dominant negative plasmids, were treated with insulin alone or with adiponectin and insulin. Effects of NIK overexpression on insulin-stimulated glucose uptake were estimated using tritiated 2-deoxyglucose uptake. NF-κB activation (EMSA), phosphatidylinositol 3 (PI3) kinase activity, and phosphorylation of inhibitor κB kinase β and serine-threonine kinase (Akt) were measured. After weight loss, skeletal muscle NIK protein was significantly reduced in association with increased plasma adiponectin and enhanced AMP kinase phosphorylation and insulin sensitivity in obese subjects. Enhanced NIK expression in cultured L6 myotubes induced a dose-dependent decrease in insulin-stimulated glucose uptake. The decrease in insulin-stimulated glucose uptake was associated with a significant decrease in PI3 kinase activity and protein kinase B/Akt phosphorylation. Overexpression of NIK kinase-dead dominant negative did not affect insulin-stimulated glucose uptake. Adiponectin treatment inhibited NIK-induced NF-κB activation and restored insulin sensitivity by restoring PI3 kinase activation and subsequent Akt phosphorylation. These results indicate that NIK induces insulin resistance and further indicate that adiponectin exerts its insulin-sensitizing effect by suppressing NIK-induced skeletal muscle inflammation. These observations suggest that NIK could be an important therapeutic target for the treatment of insulin resistance associated with inflammation in obesity and type 2 diabetes.

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Studies of the halothane-cooling contractures of skeletal muscle

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y87-115 ◽

1987 ◽

Vol 65 (4) ◽

pp. 697-703 ◽

Cited By ~ 3

Author(s):

Roberto T. Sudo ◽

Gisele Zapata ◽

Guilherme Suarez-Kurtz

Keyword(s):

Skeletal Muscle ◽

Synergistic Effects ◽

Rabbit Muscle ◽

Slow Twitch ◽

Fast Twitch ◽

Dose Dependent ◽

Muscle Biopsies ◽

Ca Homeostasis ◽

Potential Use

The characteristics of transient contractures elicited by rapid cooling of frog or mouse muscles perfused in vitro with solutions equilibrated with 0.5–2.0% halothane are reviewed. The data indicate that these halothane-cooling contractures are dose dependent and reproducible, and their amplitude is larger in muscles containing predominantly slow-twitch type fibers, such as the mouse soleus, than in muscles in which fast-twitch fibers predominate, such as the mouse extensor digitorum longus. The halothane-cooling contractures are potentiated in muscles exposed to succinylcholine. The effects of Ca2+-free solutions, of the local anesthetics procaine, procainamide, and lidocaine, and of the muscle relaxant dantrolene on the halothane-cooling contractures are consistent with the proposal that the halothane-cooling contractures result from synergistic effects of halothane and low temperature on Ca sequestration by the sarcoplasmic reticulum. Preliminary results from skinned rabbit muscle fibers support this proposal. The halothane concentrations required for the halothane-cooling contractures of isolated frog or mouse muscles are comparable with those observed in serum of patients during general anesthesia. Accordingly, fascicles dissected from muscle biopsies of patients under halothane anesthesia for programmed surgery develop large contractures when rapidly cooled. The amplitude of these halothane-cooling contractures declined with the time of perfusion of the muscle fascicles in vitro with halothane-free physiological solutions. It is suggested that the halothane-cooling contractures could be used as a simple experimental model for the investigation of the effects of halothane on Ca homeostasis and contractility in skeletal muscle and for study of drugs of potential use in the management of the contractures associated with the halothane-induced malignant hyperthermia syndrome. It is shown that salicylates, but not indomethacin or mefenamic acid, inhibit the halothane-cooling contractures.

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The Functional Role of Calcineurin in Hypertrophy, Regeneration, and Disorders of Skeletal Muscle

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/721219 ◽

2010 ◽

Vol 2010 ◽

pp. 1-8 ◽

Cited By ~ 50

Author(s):

Kunihiro Sakuma ◽

Akihiko Yamaguchi

Keyword(s):

Skeletal Muscle ◽

Functional Role ◽

Muscular Hypertrophy ◽

Growth And Remodeling ◽

Muscular Disorders ◽

Slow Twitch ◽

Fast Twitch ◽

Calcineurin Activity ◽

Muscle Remodeling

Skeletal muscle uses calcium as a second messenger to respond and adapt to environmental stimuli. Elevations in intracellular calcium levels activate calcineurin, a serine/threonine phosphatase, resulting in the expression of a set of genes involved in the maintenance, growth, and remodeling of skeletal muscle. In this review, we discuss the effects of calcineurin activity on hypertrophy, regeneration, and disorders of skeletal muscle. Calcineurin is a potent regulator of muscle remodeling, enhancing the differentiation through upregulation of myogenin or MEF2A and downregulation of the Id1 family and myostatin. Foxo may also be a downstream candidate for a calcineurin signaling molecule during muscle regeneration. The strategy of controlling the amount of calcineurin may be effective for the treatment of muscular disorders such as DMD, UCMD, and LGMD. Activation of calcineurin produces muscular hypertrophy of the slow-twitch soleus muscle but not fast-twitch muscles.

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Glutamine synthetase induction by glucocorticoids is preserved in skeletal muscle of aged rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.271.6.e1061 ◽

1996 ◽

Vol 271 (6) ◽

pp. E1061-E1066 ◽

Cited By ~ 15

Author(s):

D. Meynial-Denis ◽

M. Mignon ◽

A. Miri ◽

J. Imbert ◽

E. Aurousseau ◽

...

Keyword(s):

Skeletal Muscle ◽

Glutamine Synthetase ◽

Skeletal Muscles ◽

Female Rats ◽

Mrna Levels ◽

Aged Rats ◽

Adult Rats ◽

Adult Age ◽

Slow Twitch ◽

Fast Twitch

Glutamine synthetase (GS) is a glucocorticoid-inducible enzyme that has a key role for glutamine synthesis in muscle. We hypothesized that the glucocorticoid induction of GS could be altered in aged rats, because alterations in the responsiveness of some genes to glucocorticoids were reported in aging. We compared the glucocorticoid-induced GS in fast-twitch and slow-twitch skeletal muscles (tibialis anterior and soleus, respectively) and heart from adult (age 6-8 mo) and aged (age 22 mo) female rats. All animals received dexamethasone (Dex) in their drinking water (0.77 +/- 0.10 and 0.80 +/- 0.08 mg/day per adult and aged rat, respectively) for 5 days. Dex caused an increase in both GS activity and GS mRNA in fast-twitch and slow-twitch skeletal muscles from adult and aged rats. In contrast, Dex increased GS activity in heart of adult rats, without any concomitant change in GS mRNA levels. Furthermore, Dex did not affect GS activity in aged heart. Thus the responsiveness of GS to an excess of glucocorticoids is preserved in skeletal muscle but not in heart from aged animals.

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