Inhibition of calpain results in impaired contraction-stimulated GLUT4 translocation in skeletal muscle

Otani, Kenichi; Polonsky, Kenneth S.; Holloszy, John O.; Han, Dong‐Ho

doi:10.1152/ajpendo.00510.2005

Cited by 11 publications

(17 citation statements)

References 20 publications

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“…4). In light of reports suggesting that CaMKII might be a substrate of the Ca 2ϩ -activated protease calpain (12,25), we examined the effects of glucosamine and PUGNAc on the cleavage of ␣-fodrin, a well-characterized target for calpain (41). Consistent with these reports, we found that the cleaved 145/ 150-kDa fragment of ␣-fodrin was significantly increased during I/R compared with normoxic perfusion.…”

Section: Discussionsupporting

confidence: 69%

“…4, A and B). Otani et al (25) recently suggested that CaMKII might be a target for the Ca 2ϩ -sensitive cysteine protease calpain. This raises the possibility that the loss of total CaMKII seen here might be a consequence of calpain-mediated proteolysis and that the protection seen with glucosamine and PUGNAc could be due to attenuation of calpain activation.…”

Section: Resultsmentioning

confidence: 99%

“…Increased CaMKII activity has been implicated in contractile dysfunction following I/R (21) and also has been associated with increased apoptosis/necrosis (38). Furthermore, Otani et al (25) recently suggested that CaMKII might be a target for calpain.…”

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confidence: 99%

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IncreasedO-GlcNAc levels during reperfusion lead to improved functional recovery and reduced calpain proteolysis

Liu¹,

Marchase²,

Chatham³

2007

American Journal of Physiology-Heart and Circulatory Physiology

106

122

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We have previously shown that preischemic treatment with glucosamine improved cardiac functional recovery following ischemia-reperfusion, and this was mediated, at least in part, via enhanced flux through the hexosamine biosynthesis pathway and subsequently elevated O-linked N-acetylglucosamine (O-GlcNAc) protein levels. However, preischemic treatment is typically impractical in a clinical setting; therefore, the goal of this study was to investigate whether increasing protein O-GlcNAc levels only during reperfusion also improved recovery. Isolated perfused rat hearts were subjected to 20 min of global, no-flow ischemia followed by 60 min of reperfusion. Administration of glucosamine (10 mM) or an inhibitor of O-GlcNAcase, O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc; 200 microM), during the first 20 min of reperfusion significantly improved cardiac functional recovery and reduced troponin release during reperfusion compared with untreated control. Both interventions also significantly increased the levels of protein O-GlcNAc and ATP levels. We also found that both glucosamine and PUGNAc attenuated calpain-mediated proteolysis of alpha-fodrin as well as Ca(2+)/calmodulin-dependent protein kinase II during reperfusion. Thus two independent strategies for increasing protein O-GlcNAc levels in the heart during reperfusion significantly improved recovery, and this was correlated with attenuation of calcium-mediated proteolysis. These data provide further support for the concept that increasing cardiac O-GlcNAc levels may be a clinically relevant cardioprotective strategy and suggest that this protection could be due, at least in part, to inhibition of calcium-mediated stress responses.

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Section: Discussionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

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IncreasedO-GlcNAc levels during reperfusion lead to improved functional recovery and reduced calpain proteolysis

Liu¹,

Marchase²,

Chatham³

2007

American Journal of Physiology-Heart and Circulatory Physiology

106

122

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“…This approach ignores the fact that genes are expressed as proteins and that gene expression can be regulated at a number of steps during translation as well as posttranslationally. As an example of posttranslational regulation, it has been shown that overexpression of calpastatin, the endogenous inhibitor of the protease calpain, results in large increases in expression of GLUT4, CAMKII, and AMPK proteins despite a decrease or no change in their mRNA levels (48,49).…”

Section: Discussionmentioning

confidence: 99%

High-fat diets cause insulin resistance despite an increase in muscle mitochondria

Hancock

Han

Chen

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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469

405

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It has been hypothesized that insulin resistance is mediated by a deficiency of mitochondria in skeletal muscle. In keeping with this hypothesis, high-fat diets that cause insulin resistance have been reported to result in a decrease in muscle mitochondria. In contrast, we found that feeding rats high-fat diets that cause muscle insulin resistance results in a concomitant gradual increase in muscle mitochondria. This adaptation appears to be mediated by activation of peroxisome proliferator-activated receptor (PPAR)␦ by fatty acids, which results in a gradual, posttranscriptionally regulated increase in PPAR ␥ coactivator 1␣ (PGC-1␣) protein expression. Similarly, overexpression of PPAR␦ results in a large increase in PGC-1␣ protein in the absence of any increase in PGC-1␣ mRNA. We interpret our findings as evidence that raising free fatty acids results in an increase in mitochondria by activating PPAR␦, which mediates a posttranscriptional increase in PGC-1␣. Our findings argue against the concept that insulin resistance is mediated by a deficiency of muscle mitochondria.I t has been hypothesized that insulin resistance in patients with impaired or diabetic glucose tolerance is mediated by a deficiency of mitochondria in skeletal muscle (1, 2). The mechanism by which a decrease in mitochondria is proposed to cause insulin resistance is accumulation of intramyocellular lipids caused by a decrease in the capacity to oxidize fat (2). This hypothesis is based on the finding that type 2 diabetics and insulin-resistant individuals with impaired glucose tolerance have Ϸ30% less mitochondria in their muscles than insulinsensitive control subjects (3-7). In support of this concept, recent studies have reported that raising serum free fatty acids (FFA) by a high-fat diet in humans (8), or by feeding mice or rats high-fat diets (8-10), results in decreases in skeletal muscle peroxisome proliferator-activated receptor ␥ coactivator-1␣ (PGC-1␣) mRNA (8-10) and the mRNA levels of various mitochondrial constituents (8). In contrast, a number of earlier studies provided evidence that high-fat diets induce increases in mitochondrial marker enzymes (11-14), and Turner et al. (15) recently reported that a high-fat diet resulted in increases in mitochondrial biogenesis and fatty acid oxidative capacity in skeletal muscle of mice.We have found that raising serum FFA in rats by feeding them a high-fat diet and giving them daily heparin injections results in an increase in muscle mitochondria (16). The initial purpose of the present study was to determine whether the more modest increase in FFA induced by a high-fat diet also results in increased mitochondrial biogenesis with an increase in the capacity of muscle to oxidize fat. We found that a high-fat diet does induce an increase in muscle mitochondria. This finding made it possible to evaluate whether a high-fat diet causes muscle insulin resistance despite increases in mitochondria and fat oxidative capacity.Overexpression of peroxisome proliferator-activated receptor (PPAR)␦ i...

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“…Another recent study investigated the effect of the insulin signaling-independent muscle contraction-stimulated glucose transport in transgenic mice that overexpress the calpain inhibitor calpastatin. Despite a threeto fourfold increase in glucose transporter-4 protein, calcium calmodulin kinase II and AMP kinase in their skeletal muscles, contraction-stimulated glucose transporter-4 translocation, and glucose transport were not increased above wild type values (Otani et al 2006). These findings also suggest that the inhibition of calpain results in alterations of a step downstream of the insulin signaling pathways and/or at the level of the final effector system itself.…”

Section: Discussionmentioning

confidence: 76%

Calpain inhibition impairs glycogen syntheses in HepG2 hepatoma cells without altering insulin signaling

Meier

Klein

Kramer

et al. 2007

Journal of Endocrinology

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Calpains are a family of non-lysosomal cytoplasmatic cysteine proteases. Since calpain 10 (CAPN10), a member of the calpain family of proteases, has been found to represent a putative diabetes susceptibility gene, it was argued that calpains may be involved in the development of type 2 diabetes. The functional role of calpains in insulin signaling and/or insulin action is, however, not clear. We investigated the effects of the calpains 1 and 2 inhibitor PD151746 on insulin signaling and insulin action in human hepatoma G2 cells (HepG2 34G0 . 16 RU; P!0 . 05). Calpain inhibition with PD151746 had no effect on the insulin stimulation of the investigated insulin signaling parameters. These results in HepG2 cells suggest that calpains play a role in the hepatic regulation of insulin-stimulated glycogen synthesis independent of the PI3-kinase/Akt signaling pathway.

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Inhibition of calpain results in impaired contraction-stimulated GLUT4 translocation in skeletal muscle

Cited by 11 publications

References 20 publications

IncreasedO-GlcNAc levels during reperfusion lead to improved functional recovery and reduced calpain proteolysis

IncreasedO-GlcNAc levels during reperfusion lead to improved functional recovery and reduced calpain proteolysis

High-fat diets cause insulin resistance despite an increase in muscle mitochondria

Calpain inhibition impairs glycogen syntheses in HepG2 hepatoma cells without altering insulin signaling

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