Complete failure of insulin-transmitted signaling, but not obesity-induced insulin resistance, impairs respiratory chain function in muscle

Frankó, András; Kleist-Retzow, J. C. von; Böse, Marlen; Sánchez-Lasheras, Carmen; Brodesser, Susanne; Krut, Oleg; Kunz, Wolfram S.; Wiedermann, Dirk; Hoehn, Mathias; Stöhr, Oliver; Moll, Lorna; Freude, S.; Krone, Wilhelm; Schubert, Markus; Wiesner, Rudolf J.

doi:10.1007/s00109-012-0887-y

Cited by 36 publications

(51 citation statements)

References 50 publications

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“…Ceramides are released as products of complex sphingolipid hydrolysis or synthetized from sphingoid base (Sph or dhSph) and LCFa-CoA at the level of sarcoplasmic reticulum (45). The rise in circulating FFA and elevated muscle ceramide levels was observed previously in soleus and red gastrocnemius skeletal muscle of streptozotocin-diabetic rats (8,16) and in muscle-specific insulin receptor knockout mice and streptozotocin-treated mice (23). De novo sphingolipid synthesis depends on the supply of LCFa-CoA for both the sphingosine backbone formation by SPT and subsequent sphingosine acylation to yield ceramide.…”

Section: Discussionmentioning

confidence: 89%

“…However, not much is known about muscle sphingolipid content and composition in T1D. Intramyocellular accumulation of ceramide was observed in the streptozotocin (STZ)-diabetic rat model (8), muscle-specific insulin receptor knockout mice, and STZtreated mice (23). Thus, insulin deprivation or hypoinsulinemia leads to ceramide accumulation, but it has never been shown whether insulin treatment reverses the accumulation of ceramides in muscle.…”

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confidence: 99%

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Impact of insulin deprivation and treatment on sphingolipid distribution in different muscle subcellular compartments of streptozotocin-diabetic C57Bl/6 mice

Zabielski

Błachnio-Zabielska

Lanza

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Insulin deprivation in type 1 diabetes (T1D) individuals increases lipolysis and plasma free fatty acids (FFA) concentration, which can stimulate synthesis of intramyocellular bioactive lipids such as ceramides (Cer) and longchain fatty acid-CoAs (LCFa-CoAs). Ceramide was shown to decrease muscle insulin sensitivity, and at mitochondrial levels it stimulates reactive oxygen species production. Here, we show that insulin deprivation in streptozotocin diabetic C57BL/6 mice increases quadriceps muscle Cer content, which was correlated with a concomitant decrease in the body fat and increased plasma FFA, glycosylated hemoglobin level (%Hb A 1c), and muscular LCFa-CoA content. The alternations were accompanied by an increase in protein expression in LCFa-CoA and Cer synthesis (FATP1/ACSVL5, CerS1, CerS5), a decrease in the expression of genes implicated in muscle insulin sensitivity (GLUT4, GYS1), and inhibition of insulin signaling cascade by Akt␣ and GYS3␤ phosphorylation under acute insulin stimulation. Both the content and composition of sarcoplasmic fraction sphingolipids were most affected by insulin deprivation, whereas mitochondrial fraction sphingolipids remained stable. The observed effects of insulin deprivation were reversed, except for content and composition of LCFa-CoA, CerS protein expression, GYS1 gene expression, and phosphorylation status of Akt and GYS3␤ when exogenous insulin was provided by subcutaneous insulin implants. Principal component analysis and Pearson's correlation analysis revealed close relationships between the features of the diabetic phenotype, the content of LCFa-CoAs and Cers containing C18-fatty acids in sarcoplasm, but not in mitochondria. Insulin replacement did not completely rescue the phenotype, especially regarding the content of LCFa-CoA, or proteins implicated in Cer synthesis and muscle insulin sensitivity. These persistent changes might contribute to muscle insulin resistance observed in T1D individuals. type 1 diabetes; skeletal muscle; mitochondria; ceramide; long-chain fatty acid-coenzyme A METICULOUS GLYCEMIC CONTROL in type 1 diabetic (T1D) individuals can be achieved by administration of prandial, shortacting, and long-acting insulin to mimic ␤-cell secretion in response to varying nutrient levels. Metabolic control in these individuals and stringent adherence to guidelines normalize the plasma glucose and glycosylated hemoglobin levels (%Hb A 1c ) and allow for relatively normal life in T1D. Yet T1D individuals are at greater risk of developing cardiovascular disorders and also known to develop insulin resistance (12, 17). The molecular mechanisms responsible for insulin resistance in T1D subjects are unclear, but variable glucose concentrations (28, 70), advanced glycation end products (62, 73), or desensitization of target tissues by insulin (61) have been proposed. Subcutaneous insulin delivery using an insulin pump partially mimics ␤-cell insulin secretion. However, unlike in nondiabetic individuals with twofold higher hepatic insulin concentration than in ...

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Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 99%

Impact of insulin deprivation and treatment on sphingolipid distribution in different muscle subcellular compartments of streptozotocin-diabetic C57Bl/6 mice

Zabielski

Błachnio-Zabielska

Lanza

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Twelve-week-old mice were injected with 60 mg/kg STZ on 5 consecutive days (10). In an initial experiment, aiming at studying muscle, BEZ treatment started 8 weeks after STZ injection ( Supplementary Fig.…”

Section: Animal Studiesmentioning

confidence: 99%

“…Mitochondrial respiration was determined in soleus muscles, as described previously (10). Mitochondrial respiration was determined in digitonin-permeabilized fibroblasts using highresolution respirometry (Oxygraph-2k; Oroboros Instruments, Innsbruck, Austria).…”

Section: Oxygen Consumption Measurementsmentioning

confidence: 99%

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Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice

et al. 2016

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Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in mice with streptozotocin (STZ)-induced diabetes, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin-positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes.

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Loss of FoxOs in muscle increases strength and mitochondrial function during aging

Penniman

Bhardwaj

Nowers

et al. 2022

J cachexia sarcopenia muscle

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Background Muscle mitochondrial decline is associated with aging‐related muscle weakness and insulin resistance. FoxO transcription factors are targets of insulin action and deletion of FoxOs improves mitochondrial function in diabetes. However, disruptions in proteostasis and autophagy are hallmarks of aging and the effect of chronic inhibition of FoxOs in aged muscle is unknown. This study investigated the role of FoxOs in regulating muscle strength and mitochondrial function with age. Methods We measured muscle strength, cross‐sectional area, muscle fibre‐type, markers of protein synthesis/degradation, central nuclei, glucose/insulin tolerance, and mitochondrial bioenergetics in 4.5‐month (Young) and 22–24‐month‐old (Aged) muscle‐specific FoxO1/3/4 triple KO (TKO) and littermate control (Ctrl) mice. Results Lean mass was increased in Aged TKO compared with both Aged Ctrl and younger groups by 26–33% (P < 0.01). Muscle strength, measured by max force of tibialis anterior (TA) contraction, was 20% lower in Aged Ctrl compared with Young Ctrls (P < 0.01) but was not decreased in Aged TKOs. Increased muscle strength in Young and Aged TKO was associated with 18–48% increased muscle weights compared with Ctrls (P < 0.01). Muscle cross‐sectional analysis of TA, soleus, and plantaris revealed increases in fibre size distribution and a 2.5–10‐fold increase in central nuclei in Young and Aged TKO mice, without histologic signs of muscle damage. Age‐dependent increases in Gadd45a and Ube4a expression as well accumulation of K48 polyubiquitinated proteins were observed in quad and TA but were prevented by FoxO deletion. Young and Aged TKO muscle showed minimal changes in autophagy flux and no accumulation of autophagosomes compared with Ctrl groups. Increased strength in Young and Aged TKO was associated with a 10–20% increase in muscle mitochondrial respiration using glutamate/malate/succinate compared with controls (P < 0.05). OXPHOS subunit expression and complex I activity were decreased 16–34% in Aged Ctrl compared with Young Ctrl but were prevented in Aged TKO. Both Aged Ctrl and Aged TKO showed impaired glucose tolerance by 33% compared to young groups (P < 0.05) indicating improved strength and mitochondrial respiration are not due to improved glycemia. Conclusions FoxO deletion increases muscle strength even during aging. Deletion of FoxOs maintains muscle strength in part by mild suppression of atrophic pathways, including inhibition of Gadd45a and Ube4a expression, without accumulation of autophagosomes in muscle. Deletion of FoxOs also improved mitochondrial function by maintenance of OXPHOS in both young and aged TKO.

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Complete failure of insulin-transmitted signaling, but not obesity-induced insulin resistance, impairs respiratory chain function in muscle

Abstract: © 2012 Springer-Verla

Cited by 36 publications

References 50 publications

Impact of insulin deprivation and treatment on sphingolipid distribution in different muscle subcellular compartments of streptozotocin-diabetic C57Bl/6 mice

Impact of insulin deprivation and treatment on sphingolipid distribution in different muscle subcellular compartments of streptozotocin-diabetic C57Bl/6 mice

Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice

Loss of FoxOs in muscle increases strength and mitochondrial function during aging

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