Involvement of the rapamycin-sensitive pathway in the insulin regulation of muscle protein synthesis in streptozotocin-diabetic rats

Grzelkowska, K.; Dardevet, Dominique; Balage, Michèle; Grizard, Jean

doi:10.1677/joe.0.1600137

Cited by 17 publications

(13 citation statements)

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“…While a reduced protein synthesis with STZ treatment could explain the decrease in fiber area, previous reports (18) indicate that protein synthesis rates are restored when insulin levels are reestablished in STZ-treated rats. It may be that a reduced food intake and/or an increase in glucocorticoids in the STZ and STZ-INS rats could explain, at least in part, the apparent to label all nuclei and dichlorofluorescein (green) to label ROS.…”

Section: Discussionmentioning

confidence: 86%

Streptozotocin induces G₂arrest in skeletal muscle myoblasts and impairs muscle growth in vivo

Johnston

Campbell²,

Found³

et al. 2007

American Journal of Physiology-Cell Physiology

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Streptozotocin (STZ) is used extensively to induce pancreatic beta-cell death and ultimately diabetes mellitus in animal models. However, the direct effects of STZ on muscle are largely unknown. To delineate the effects of STZ from the effects of hypoinsulinemia/hyperglycemia, we injected young rats with 1) saline (control), 2) STZ (120 mg/kg) or 3) STZ and insulin (STZ-INS; to maintain euglycemia). STZ rats demonstrated significantly elevated blood glucose throughout the 48-h protocol, while control and STZ-INS rats were euglycemic. Body mass increased in control (13 +/- 4 g), decreased by 19 +/- 2 g in STZ and remained unchanged in STZ-INS rats (-0.3 +/- 2 g). Cross-sectional areas of gastrocnemius muscle fibers were smaller in STZ vs. control (1,480 +/- 149 vs. 1,870 +/- 40 microm(2), respectively; P < 0.05) and insulin treatment did not rescue this defect (STZ-INS: 1,476 +/- 143 microm(2)). Western blot analysis revealed a detectable increase in ubiquitinated proteins in the STZ skeletal muscles compared with control and STZ-INS. To further define the effects of STZ on skeletal muscle, independent of hyperglycemia, myoblasts were exposed to varying doses of STZ (0.25-3.0 mg/ml) in vitro. Both acute and chronic exposures of STZ significantly impaired proliferative capacity in a dose-dependent manner. Within STZ-treated myoblasts, increased reactive oxygen species was associated with significant G(2)/M phase cell-cycle arrest. Taken together, our findings show that the effects of STZ are not beta-cell specific and reveal that STZ should not be used for studies examining diabetic myopathy.

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Section: Discussionmentioning

confidence: 86%

Streptozotocin induces G₂arrest in skeletal muscle myoblasts and impairs muscle growth in vivo

Johnston

Campbell²,

Found³

et al. 2007

American Journal of Physiology-Cell Physiology

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“…Grzelkowska et al (42) reported that rapamycin, an inhibitor of mTOR, reduces insulin-stimulated rates of protein synthesis in isolated epitrochlearis muscle of control rats to 64% of values obtained in muscles incubated in the absence of the inhibitor. In contrast, rapamycin further attenuates rates of insulin-stimulated protein synthesis in muscle isolated from streptozotocininduced diabetic rats to 32% of values reported in diabetic controls.…”

Section: Discussionmentioning

confidence: 99%

Orally Administered Leucine Enhances Protein Synthesis in Skeletal Muscle of Diabetic Rats in the Absence of Increases in 4E-BP1 or S6K1 Phosphorylation

et al. 2002

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In this study, food-deprived (18 h) control rats and rats with alloxan-induced diabetes were orally administered saline or the amino acid leucine to assess whether it regulates protein synthesis independently of a change in serum insulin concentrations. Immediately after leucine administration, diabetic rats were infused with insulin (0.0, 4.0, or 20 pmol ⅐ min -1 ⅐ kg -1 ) for 1 h to examine the role of the hormone in the protein synthetic response to leucine. In control rats, leucine stimulated protein synthesis by 58% and increased phosphorylation of the translational repressor, eukaryotic initiation factor (eIF) 4E-binding protein (BP)-1, 4E-BP1, fivefold. Consequently, association of the mRNA cap-binding protein eukaryotic initiation factor (eIF)4E with 4E-BP1 was reduced to 50% of control values, and eIF4G•eIF4E complex assembly was increased 80%. Furthermore, leucine increased the phosphorylation of the 70-kDa ribosomal protein S6 (rp S6) and the ribosomal protein S6 kinase (S6K1). Diabetes attenuated protein synthesis compared with control rats. Nonetheless, in diabetic rats, leucine increased protein synthesis by 53% without concomitant changes in the phosphorylation of 4E-BP1 or S6K1. Skeletal muscle protein synthesis was stimulated in diabetic rats infused with insulin, but rates of synthesis remained less than values in nondiabetic controls that were administered leucine. Phosphorylation of 4E-BP1 and S6K1 was increased in diabetic rats infused with insulin in a dose-dependent manner, and the response was enhanced by leucine. The results suggest that leucine enhances protein synthesis in skeletal muscle through both insulin-dependent and -independent mechanisms. The insulin-dependent mechanism is associated with increased phosphorylation of 4E-BP1 and S6K1. In contrast, the insulin-independent effect on protein synthesis is mediated by an unknown mechanism. Diabetes 51: -936, 2002A fter consumption of a protein-containing meal, the fractional rate of protein synthesis of total mixed proteins in skeletal muscle of growing animals is upregulated. Two vital components of this response are elevations in circulating concentrations of the hormone insulin and an increase in amino acid supply. The relative importance of each of these components in regulating protein synthesis continues to be a topic of investigation and controversy. Several reports indicate that physiological increases in circulating insulin concentrations are not sufficient to stimulate protein synthesis in food-deprived rats (1-4). When postabsorptive rats are administered an oral bolus of carbohydrate alone, no change in protein synthesis is observed. In contrast, when food-deprived rats are administered an isocaloric macronutrient-mixed meal, rates of protein synthesis are stimulated (1). Plasma insulin concentrations in rats administered either meal are similar; hence, the enhanced rate of recovery in rats administered a mixed meal cannot be attributed to a differential insulin response between the groups. Likewise, when fasted rats are...

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“…Loss of skeletal muscle, with enhanced protein breakdown, has been demonstrated in rats with experimental diabetes (1,2) as well as in type 1 diabetic patients (3). Conversely, although there is general agreement that insulin withdrawal affects fractional protein synthesis rates, the precise mechanism of impaired muscle repair in diabetes is not fully understood (4,5).…”

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confidence: 99%

Oxidative Stress Impairs Skeletal Muscle Repair in Diabetic Rats

et al. 2004

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Alongside increased proteolysis, the inability to repair damaged skeletal muscle is a characteristic feature of uncontrolled diabetes. This study evaluates the role of oxidative stress in muscle-specific gene regulatory regions and myosin chain synthesis in streptozotocin (STZ)-induced diabetic and ZDF rats. In the gastrocnemius muscle of diabetic rats, prooxidant compounds were seen to increase while antioxidant levels fell. Myogenic regulatory factors-Myo, myogenin, and Jun D-were also reduced, and muscle enhancer factor (MEF)-1 DNA binding activity was impaired. Moreover, synthesis of muscle creatine kinase and both heavy and light chains of myosin were impaired, suggesting that oxidative stress triggers the cascade of events that leads to impaired muscle repair. Dehydroepiandrosterone has been reported to possess antioxidant properties. When it was administered to diabetic rats, in addition to an improved oxidative imbalance there was a recovery of myogenic factors, MEF-1 DNA binding activity, synthesis of muscle creatine kinase, and myosin light and heavy chains. Vitamin E administration to STZ-induced diabetic rats reverses oxidative imbalance and improves muscle gene transcription, reinforcing the suggestion that oxidative stress may play a role in diabetes-related impaired muscle repair. Diabetes

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Involvement of the rapamycin-sensitive pathway in the insulin regulation of muscle protein synthesis in streptozotocin-diabetic rats

Cited by 17 publications

References 50 publications

Streptozotocin induces G₂arrest in skeletal muscle myoblasts and impairs muscle growth in vivo

Streptozotocin induces G₂arrest in skeletal muscle myoblasts and impairs muscle growth in vivo

Orally Administered Leucine Enhances Protein Synthesis in Skeletal Muscle of Diabetic Rats in the Absence of Increases in 4E-BP1 or S6K1 Phosphorylation

Oxidative Stress Impairs Skeletal Muscle Repair in Diabetic Rats

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Involvement of the rapamycin-sensitive pathway in the insulin regulation of muscle protein synthesis in streptozotocin-diabetic rats

Cited by 17 publications

References 50 publications

Streptozotocin induces G2arrest in skeletal muscle myoblasts and impairs muscle growth in vivo

Streptozotocin induces G2arrest in skeletal muscle myoblasts and impairs muscle growth in vivo

Orally Administered Leucine Enhances Protein Synthesis in Skeletal Muscle of Diabetic Rats in the Absence of Increases in 4E-BP1 or S6K1 Phosphorylation

Oxidative Stress Impairs Skeletal Muscle Repair in Diabetic Rats

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Streptozotocin induces G₂arrest in skeletal muscle myoblasts and impairs muscle growth in vivo

Streptozotocin induces G₂arrest in skeletal muscle myoblasts and impairs muscle growth in vivo