Glucose Metabolism In Skeletal Muscle Research Articles

Identification of novel indole derivatives as highly potent AMPK activators with anti-diabetic profiles

AMP-activated protein kinase (AMPK) has been shown to play an important role in the beneficial effects of exercise on glucose and lipid metabolism in skeletal muscle and liver. Therefore, activation of AMPK has been proposed as an attractive strategy for the treatment of metabolic disorders, such as type 2 diabetes. Many of existing AMPK activators bearing diverse chemical structure were reported. However, there have been few reports of direct AMPK activator with high potency for β2-AMPK isoform, which is thought to be important for glucose homeostasis, and their chemical structure is limited to benzimidazole core. We describe herein our efforts for identification of novel AMPK activator. Our newly designed 4-azaindole derivative 16g exhibited single-digit nM in vitro activity, and chronic treatment with 16g led to dose-dependent improvement in HbA1c as well as decrease in hepatic lipid accumulation in diabetic animal model.

Sesamol counteracts on metabolic disorders of middle-aged alimentary obese mice through regulating skeletal muscle glucose and lipid metabolism.

BackgroundGlobally, obesity is a significant public problem, especially when aging. Sesamol, a phenolic lignan present in sesame seeds, might have a positive effect on high-fat diet (HFD)-induced obesity associated with aging.ObjectiveThe purpose of current research study was to explore salutary effects and mechanisms of sesamol in treating alimentary obesity and associated metabolic syndrome in middle-aged mice.MethodsC57BL/6J mice aged 4–6 weeks and 6–8 months were assigned to the young normal diet group, middle-aged normal diet group, middle-aged HFD group, and middle-aged HFD + sesamol group. At the end of experiment, glucose tolerance test and insulin tolerance test were performed; the levels of lipids and oxidative stress-related factors in the serum and skeletal muscle were detected using chemistry reagent kits; lipid accumulation in skeletal muscle was observed by oil red O staining; the expressions of muscular glucose and lipid metabolism associated proteins were measured by Western blotting.ResultsSesamol decreased the body weight and alleviated obesity-associated metabolism syndrome in middle-aged mice, such as glucose intolerance, insulin resistance, dyslipidemia, and oxidative stress. Moreover, muscular metabolic disorders were attenuated after treatment with sesamol. It increased the expression of glucose transporter type-4 and down-regulated the protein levels of pyruvate dehydrogenase kinase isozyme 4, implying the increase of glucose uptake and oxidation. Meanwhile, sesamol decreased the expression of sterol regulatory element binding protein 1c and up-regulated the phosphorylation of hormone-sensitive lipase and the level of carnitine palmityl transferase 1α, which led to the declined lipogenesis and the increased lipolysis and lipid oxidation. In addition, the SIRT1/AMPK signaling pathway was triggered by sesamol, from which it is understood how sesamol enhances glucose and lipid metabolism.ConclusionsSesamol counteracts on metabolic disorders of middle-aged alimentary obese mice through regulating skeletal muscle glucose and lipid metabolism, which might be associated with the stimulation of the SIRT1/AMPK pathway.

Prenatal Low-Protein Diet Affects Mitochondrial Structure and Function in the Skeletal Muscle of Adult Female Offspring.

Gestational low-protein (LP) diet leads to glucose intolerance and insulin resistance in adult offspring. We had earlier demonstrated that LP programming affects glucose disposal in females. Mitochondrial health is crucial for normal glucose metabolism in skeletal muscle. In this study, we sought to analyze mitochondrial structure, function, and associated genes in skeletal muscles to explore the molecular mechanism of insulin resistance LP-programmed female offspring. On day four of pregnancy, rats were assigned to a control diet containing 20% protein or an isocaloric 6% protein-containing diet. Standard laboratory diet was given to the dams after delivery until the end of weaning and to pups after weaning. Gestational LP diet led to changes in mitochondrial ultrastructure in the gastrocnemius muscles, including a nine-fold increase in the presence of giant mitochondria along with unevenly formed cristae. Further, functional analysis showed that LP programming caused impaired mitochondrial functions. Although the mitochondrial copy number did not show significant changes, key genes involved in mitochondrial structure and function such as Fis1, Opa1, Mfn2, Nrf1, Nrf2, Pgc1b, Cox4b, Esrra, and Vdac were dysregulated. Our study shows that prenatal LP programming induced disruption in mitochondrial ultrastructure and function in the skeletal muscle of female offspring.

Astaxanthin Exerts Anabolic Effects via Pleiotropic Modulation of the Excitable Tissue.

Astaxanthin is a lipid-soluble carotenoid influencing lipid metabolism, body weight, and insulin sensitivity. We provide a systematic analysis of acute and chronic effects of astaxanthin on different organs. Changes by chronic astaxanthin feeding were analyzed on general metabolism, expression of regulatory proteins in the skeletal muscle, as well as changes of excitation and synaptic activity in the hypothalamic arcuate nucleus of mice. Acute responses were also tested on canine cardiac muscle and different neuronal populations of the hypothalamic arcuate nucleus in mice. Dietary astaxanthin significantly increased food intake. It also increased protein levels affecting glucose metabolism and fatty acid biosynthesis in skeletal muscle. Inhibitory inputs innervating neurons of the arcuate nucleus regulating metabolism and food intake were strengthened by both acute and chronic astaxanthin treatment. Astaxanthin moderately shortened cardiac action potentials, depressed their plateau potential, and reduced the maximal rate of depolarization. Based on its complex actions on metabolism and food intake, our data support the previous findings that astaxanthin is suitable for supplementing the diet of patients with disturbances in energy homeostasis.

Spexin ameliorates skeletal muscle insulin resistance through activation of GAL2 receptor

Skeletal muscle is a principal tissue involved in energy expenditure and glucose metabolism. Although the results of our and other studies show that spexin could decrease food intake and obesity, the specific metabolic effect of spexin on glucose metabolism of skeletal muscle is still unclear. The aim of this study is to investigate whether spexin might mitigate obesity-induced insulin resistance in skeletal muscles and to explore its underlying mechanisms. The high fat diet-fed mice were treated with 50 μg/kg/d spexin for 21 consecutive days, and the differentiated myotubes of L6 were treated with spexin (200, 400, 800 nM) in the absence or presence of M871 (800 nM) for 12 h respectively. Besides, the galanin type 2 (GAL2) receptor knockdown myotubes were treated with 800 nM spexin for 12 h in this study. The present findings showed that spexin reversed hyperglycemia and glucose intolerance as well as insulin intolerance and insulin resistance in the mice fed with high fat diet. Furthermore, spexin markedly augmented the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) expression and deacetylation, and further triggered glucose transporter 4 (GLUT4) expression and trafficking in myotubes through p38 mitogen-activated protein kinase (P38MAPK) and protein kinase B (AKT) activation. More importantly, the elevation of glucose consumption related genes by spexin were abolished by GAL2 receptor antagonist or silencing of GAL2 receptor in myotubes. In conclusion, our findings provide a novel insight that spexin can protect against insulin resistance and increase glucose consumption in skeletal muscles mainly through activation of GAL2/GLUT4 signal pathway. Spexin might therefore be a novel therapeutic target for hyperglycemia and insulin resistance in clinic.

Deficits in skeletal muscle glucose metabolism and whole-body oxidative metabolism in the intrauterine growth-restricted juvenile lamb are improved by daily treatment with clenbuterol

Deficits in skeletal muscle glucose metabolism and whole-body oxidative metabolism in the intrauterine growth-restricted juvenile lamb are improved by daily treatment with clenbuterol

Endurance exercise training-responsive miR-19b-3p improves skeletal muscle glucose metabolism

Skeletal muscle is a highly adaptable tissue and remodels in response to exercise training. Using short RNA sequencing, we determine the miRNA profile of skeletal muscle from healthy male volunteers before and after a 14-day aerobic exercise training regime. Among the exercise training-responsive miRNAs identified, miR-19b-3p was selected for further validation. Overexpression of miR-19b-3p in human skeletal muscle cells increases insulin signaling, glucose uptake, and maximal oxygen consumption, recapitulating the adaptive response to aerobic exercise training. Overexpression of miR-19b-3p in mouse flexor digitorum brevis muscle enhances contraction-induced glucose uptake, indicating that miR-19b-3p exerts control on exercise training-induced adaptations in skeletal muscle. Potential targets of miR-19b-3p that are reduced after aerobic exercise training include KIF13A, MAPK6, RNF11, and VPS37A. Amongst these, RNF11 silencing potentiates glucose uptake in human skeletal muscle cells. Collectively, we identify miR-19b-3p as an aerobic exercise training-induced miRNA that regulates skeletal muscle glucose metabolism.

The outstanding beneficial roles of irisin disorders.

Depression is a widely observed psychiatric disorder that affects a quite large number of people all around the world. A major depressive disorder (MDD) is a multifactorial disease that IS associated with fluctuations in appetite, body weight, and energy situations in addition to serious mood problems. The aim of this review is to investigate a possible link between energy regulatory hormones of irisin and depressive disorders. Irisin is a hormone that plays a significant role in the regulation of lipid and glucose metabolism in skeletal muscle and adipose tissue. Irisin was also reported to play significant roles in the central nervous system. In the literature there are reports indicating a beneficial antidepressant role of irisin in MDD. It should be emphasised that the antidepressive effects of exercise could be the result of exercise-induced increased hormones of irisin.

The Effect of Exercise Timing on Elevated Postprandial Glucose in Women With Obesity

Background and Aim: This study aimed to investigate the effect of exercise timing on elevated postprandial glucose and after brief interval exercises in women with obesity. Methods & Materials: Ten women with obesity (Mean±SD age = 40.41±3.97 years; weight = 86.66±7.26 kg; and BMI = 33.22±2.20 kg/m2) participated in a crossover design exercise intervention: 1) postprandial aerobic exercise, 2) pre-prandial aerobic exercise, 3) brief periodic exercise, and 4) control. Pre- and postprandial exercise included 30 min of moderate-intensity walking on the treadmill before and after each main meal (1 minute of exercise -30 seconds rest). The brief periodic exercise had three one-minute reps of activity every 30 min for 20 times during the day. Twelve-hour continuous glucose monitoring and two-hour postprandial glucose levels were calculated to examine changes in blood glucose levels. Ethical Considerations: This study was approved by the institutional review board of the University of Isfahan (Ethics Code: IR.UI.REC.1397.119) and conducted in agreement with the ethical principles for biomedical research involving human subjects outlined in the declaration of Helsinki. Results: The findings of this study suggested that brief periodic exercise resulted in a significant decrease in continuous glucose monitoring levels and postprandial glucose compared to the control group as well as pre-prandial exercise (P˂0.05). However, pre- and postprandial exercise did not result in significant changes in continuous glucose monitoring (P˃0.05). In addition, postprandial exercise led to a significant decrease in postprandial glucose compared to the control group (P˂0.05). Conclusion: It seems that brief periodic exercise can have more beneficial effects on postprandial glucose levels, probably due to improved glucose metabolism in skeletal muscle.

Low-Dose Acrolein, an Endogenous and Exogenous Toxic Molecule, Inhibits Glucose Transport via an Inhibition of Akt-Regulated GLUT4 Signaling in Skeletal Muscle Cells.

Urinary acrolein adduct levels have been reported to be increased in both habitual smokers and type-2 diabetic patients. The impairment of glucose transport in skeletal muscles is a major factor responsible for glucose uptake reduction in type-2 diabetic patients. The effect of acrolein on glucose metabolism in skeletal muscle remains unclear. Here, we investigated whether acrolein affects muscular glucose metabolism in vitro and glucose tolerance in vivo. Exposure of mice to acrolein (2.5 and 5 mg/kg/day) for 4 weeks substantially increased fasting blood glucose and impaired glucose tolerance. The glucose transporter-4 (GLUT4) protein expression was significantly decreased in soleus muscles of acrolein-treated mice. The glucose uptake was significantly decreased in differentiated C2C12 myotubes treated with a non-cytotoxic dose of acrolein (1 μM) for 24 and 72 h. Acrolein (0.5–2 μM) also significantly decreased the GLUT4 expression in myotubes. Acrolein suppressed the phosphorylation of glucose metabolic signals IRS1, Akt, mTOR, p70S6K, and GSK3α/β. Over-expression of constitutive activation of Akt reversed the inhibitory effects of acrolein on GLUT4 protein expression and glucose uptake in myotubes. These results suggest that acrolein at doses relevant to human exposure dysregulates glucose metabolism in skeletal muscle cells and impairs glucose tolerance in mice.

Gliquidone ameliorates hepatic insulin resistance in streptozotocin-induced diabetic Sur1−/− rats

Gliquidone was suggested to exert hypoglycemic effect through enhancing hepatic insulin sensitivity. However, inadequate in vivo evidences make this statement controversial. The aim of the present study was to clarify the insulin-sensitizer role of gliquidone in liver and muscle, so as to confirm its extra-pancreatic effects in vivo. TALEN technique was used to create Sur1 knockout (Sur1−/−) rats. Diabetic Sur1−/− rat models were established by high-fat diet combined with streptozotocin, and which were randomly divided into three groups: gliquidone, metformin and saline, treated for 8 weeks. Fasting blood glucose (FBG) and body mass were tested each week. IPGTT, IPITT and hyperinsulinemic-euglycemic clamp tests were used to evaluate glucose tolerance and insulin sensitivity, respectively. Key mediators of glucose metabolism in liver and skeletal muscle and the activity of AKT and AMPK in these tissues were further analyzed. We found that gliquidone decreased FBG and increased insulin sensitivity without increasing insulin secretion in diabetic Sur1−/− rats. Further exploration implied that gliquidone mainly increased hepatic glycogen storage and decreased gluconeogenesis, which were accompanied with activation of AKT, but not enhanced muscle GLUT4 expression. However, both these effects were still weaker than that of metformin. These results suggested that gliquidone could exerts an extra-pancreatic hypoglycemic effect by improving insulin sensitivity, which might be largely attributes to its additional insulin sensitizer role in hepatic glucose metabolism.

Prenylflavonoids from fruit of Macaranga tanarius promote glucose uptake via AMPK activation in L6 myotubes.

Skeletal muscle is a major tissue of glucose consumption and plays an important role in glucose homeostasis. Prenylflavonoids, a component of Macaranga tanarius fruits, have been reported to have antioxidant, antibacterial, and anticancer effects. However, the effects of these compounds on skeletal muscle glucose metabolism are unclear. Here, we isolated five prenylflavonoids from M. tanarius fruits, and investigated the mechanism of action of these compounds on skeletal muscle cells using L6 myotubes. We found that isonymphaeol B and 3'-geranyl naringenin increased glucose uptake in a dose-dependent manner. Furthermore, both isonymphaeol B and 3'-geranyl naringenin increased AMPK phosphorylation but did not affect PI3K-Akt phosphorylation. Isonymphaeol B and 3'-geranyl naringenin also increased Glut1 mRNA expression and plasma membrane GLUT1 protein levels. These results suggest that isonymphaeol B and 3'-geranyl naringenin have beneficial effects on glucose metabolism through AMPK and GLUT1 pathway. Isonymphaeol B and 3'-geranyl naringenin may be potential lead candidates for antidiabetic drug development.

AXIN1 knockout does not alter AMPK/mTORC1 regulation and glucose metabolism in mouse skeletal muscle.

Tamoxifen-inducible skeletal muscle-specific AXIN1 knockout (AXIN1 imKO) in mouse does not affect whole-body energy substrate metabolism. AXIN1 imKO does not affect AICAR or insulin-stimulated glucose uptake in adult skeletal muscle. AXIN1 imKO does not affect adult skeletal muscle AMPK or mTORC1 signalling during AICAR/insulin/amino acid incubation, contraction and exercise. During exercise, α2/β2/γ3AMPK and AMP/ATP ratio show greater increases in AXIN1 imKO than wild-type in gastrocnemius muscle. AXIN1 is a scaffold protein known to interact with >20 proteins in signal transduction pathways regulating cellular development and function. Recently, AXIN1 was proposed to assemble a protein complex essential to catabolic-anabolic transition by coordinating AMPK activation and inactivation of mTORC1 and to regulate glucose uptake-stimulation by both AMPK and insulin. To investigate whether AXIN1 is permissive for adult skeletal muscle function, a phenotypic in vivo and ex vivo characterization of tamoxifen-inducible skeletal muscle-specific AXIN1 knockout (AXIN1 imKO) mice was conducted. AXIN1 imKO did not influence AMPK/mTORC1 signalling or glucose uptake stimulation at rest or in response to different exercise/contraction protocols, pharmacological AMPK activation, insulin or amino acids stimulation. The only genotypic difference observed was in exercising gastrocnemius muscle, where AXIN1 imKO displayed elevated α2/β2/γ3 AMPK activity and AMP/ATP ratio compared to wild-type mice. Our work shows that AXIN1 imKO generally does not affect skeletal muscle AMPK/mTORC1 signalling and glucose metabolism, probably due to functional redundancy of its homologue AXIN2.

Maternofetal inflammation induced for 2 wk in late gestation reduced birth weight and impaired neonatal growth and skeletal muscle glucose metabolism in lambs.

Intrauterine stress impairs growth and metabolism in the fetus and offspring. We recently found that sustained maternofetal inflammation resulted in intrauterine growth-restricted (MI-IUGR) fetuses with asymmetric body composition, impaired muscle glucose metabolism, and β-cell dysfunction near term. These fetuses also exhibited heightened inflammatory tone, which we postulated was a fetal programming mechanism for the IUGR phenotype. Thus, the objective of this study was to determine whether poor growth and metabolism persisted in MI-IUGR lambs after birth. Polypay ewes received serial lipopolysaccharide or saline injections in the first 2 wk of the third trimester of pregnancy to produce MI-IUGR (n = 13) and control (n = 12) lambs, respectively. Lambs were catheterized at 25 d of age. β-Cell function was assessed at 29 d, hindlimb glucose metabolism at 30 d, and daily blood parameters from day 26 to 31. Glucose metabolism was also assessed in flexor digitorum superficialis (FDS) muscle isolated at necropsy on day 31. Asymmetric body composition persisted in MI-IUGR neonates, as these lambs were lighter (P < 0.05) than controls at birth and 31 d, but body and cannon bone lengths did not differ at either age. FDS muscles from MI-IUGR lambs were smaller (P < 0.05) and exhibited reduced (P < 0.05) glucose oxidation and Akt phosphorylation but similar glucose uptake compared with controls when incubated in basal or insulin-spiked media. Similarly, hindlimb glucose oxidation was reduced (P < 0.05) in MI-IUGR lambs under basal and hyperinsulinemic conditions, but hindlimb glucose utilization did not differ from controls. Circulating urea nitrogen and cholesterol were reduced (P < 0.05), and triglycerides, high-density lipoprotein cholesterol, and glucose-to-insulin ratios were increased (P < 0.05) in MI-IUGR lambs. Glucose and insulin concentrations did not differ between groups during basal or hyperglycemic conditions. Although circulating monocyte and granulocyte concentrations were greater (P < 0.05) in MI-IUGR lambs, plasma tumor necrosis factor α (TNFα) was reduced (P < 0.05). FDS muscle contained greater (P < 0.05) TNF receptor 1 (TNFR1) and IκBα protein content. These findings indicate that maternofetal inflammation in late pregnancy results in fetal programming that impairs growth capacity, muscle glucose oxidation, and lipid homeostasis in offspring. Inflammatory indicators measured in this study appear to reflect heightened cytokine sensitivity in muscle and compensatory systemic responses to it.

Photobiomodulation therapy ameliorates hyperglycemia and insulin resistance by activating cytochrome c oxidase-mediated protein kinase B in muscle.

Ameliorating hyperglycemia and insulin resistance are major therapeutic strategies for type 2 diabetes. Previous studies have indicated that photobiomodulation therapy (PBMT) attenuates metabolic abnormalities in insulin-resistant adipose cells and tissues. However, it remains unclear whether PBMT ameliorates glucose metabolism in skeletal muscle in type 2 diabetes models. Here we showed that PBMT reduced blood glucose and insulin resistance, and reversed metabolic abnormalities in skeletal muscle in two diabetic mouse models. PBMT accelerated adenosine triphosphate (ATP) and reactive oxygen species (ROS) generation by elevating cytochrome c oxidase (CcO) activity. ROS-induced activation of phosphatase and tensin homolog (PTEN)/ protein kinase B (AKT) signaling after PBMT promoted glucose transporter GLUT4 translocation and glycogen synthase (GS) activation, accelerating glucose uptake and glycogen synthesis in skeletal muscle. CcO subunit III deficiency, ROS elimination, and AKT inhibition suppressed the PBMT effects of glucose metabolism in skeletal muscle. This study indicated amelioration of glucose metabolism after PBMT in diabetic mouse models and revealed the metabolic regulatory effects and mechanisms of PBMT on skeletal muscle.

Effects of rosiglitazone on growth and skeletal muscle glucose metabolism of GIFT tilapia based on PI3K/Akt signaling pathway

This study aimed to investigate the effects of rosiglitazone on glucose metabolism of GIFT tilapia based on the PI3K/Akt signalling pathway. The experiment was divided into five groups: normal starch group (32%, LC), high starch group (53%, HC), HC + rosiglitazone group 1 (10 mg/kg, R1), HC + rosiglitazone group 2 (20 mg/kg, R2) and HC + rosiglitazone group 3 (30 mg/kg, R3). The results showed that a high starch diet added with 10–20 mg/kg rosiglitazone had a better specific growth rate and protein efficiency that was beneficial for the growth of the tilapia. With an increase in the rosiglitazone concentration, the contents of serum glucose, insulin and hepatic glycogen in the R1, R2 and R3 groups decreased gradually. Meanwhile, the muscle glycogen content in the R1, R2 and R3 groups increased gradually. The mRNA expression of the IRS-1, PI3K, GLUT-4 and Akt proteins in the R1, R2 and R3 groups was significantly higher than that in the HC group (p < 0.05). Compared with the HC group, the expression of the GSK-3 mRNA in the R1, R2 and R3 groups was significantly reduced (p < 0.05). The protein expression of p-GSK-3β (phosphorylated GSK-3β) in the R1 and R2 groups was significantly higher than that in the HC group (p < 0.05). In conclusion, a high starch diet supplemented with rosiglitazone can improve growth, enhanced the serum biochemical indices and increase the muscle glycogen content in the GIFT tilapia. It benefits in upregulating the IRS-1, PI3K and GLUT-4 mRNA in the skeletal muscle and promotes glucose uptake. Meanwhile, the phosphorylation of Akt and GSK-3β increased significantly and resulted in the inactivation of GSK-3β and alleviation of insulin resistance. Under these experimental conditions, the optimal dosage of rosiglitazone on tilapia was 10–20 mg/kg diet.

Plant-Derived Trans-β-Caryophyllene Boosts Glucose Metabolism and ATP Synthesis in Skeletal Muscle Cells through Cannabinoid Type 2 Receptor Stimulation.

Skeletal muscle plays a pivotal role in whole-body glucose metabolism, accounting for the highest percentage of glucose uptake and utilization in healthy subjects. Impairment of these key functions occurs in several conditions including sedentary lifestyle and aging, driving toward hyperglycemia and metabolic chronic diseases. Therefore, strategies pointed to improve metabolic health by targeting skeletal muscle biochemical pathways are extremely attractive. Among them, we focused on the natural sesquiterpene and cannabinoid type 2 (CB2) receptor agonist Trans-β-caryophyllene (BCP) by analyzing its role in enhancing glucose metabolism in skeletal muscle cells. Experiments were performed on C2C12 myotubes. CB2 receptor membrane localization in myotubes was assessed by immunofluorescence. Within glucose metabolism, we evaluated glucose uptake (by the fluorescent glucose analog 2-NBDG), key enzymes of both glycolytic and oxidative pathways (by spectrophotometric assays and metabolic radiolabeling) and ATP production (by chemiluminescence-based assays). In all experiments, CB2 receptor involvement was tested with the CB2 antagonists AM630 and SR144528. Our results show that in myotubes, BCP significantly enhances glucose uptake, glycolytic and oxidative pathways, and ATP synthesis through a CB2-dependent mechanism. Giving these outcomes, CB2 receptor stimulation by BCP could represent an appealing tool to improve skeletal muscle glucose metabolism, both in physiological and pathological conditions.

Skeletal muscle metabolism on whole-body positron emission tomography during pitching

BackgroundElectromyography (EMG) has been used for evaluating skeletal muscle activity during pitching. However, it is difficult to observe the influence of movement on skeletal muscle activity in deep-lying regions of the trunk and extremities using EMG. An alternative method that may be used is the measurement of glucose metabolism of skeletal muscle using positron emission tomography-computed tomography (PET-CT). This technique is a reliable measure of muscle metabolism, demonstrating a high correlation with the intensity of muscle activity. This study aimed to evaluate whole-body skeletal muscle metabolism during pitching using PET-CT.MethodsTen uninjured, skilled, adult pitchers, who were active at college or professional level, threw 40 baseballs at maximal effort before an intravenous injection of 37 MBq of 18F-fluorodeoxyglucose (FDG). Subsequently, additional 40 balls were pitched. PET-CT images were obtained 50 min after FDG injection, and regions of interest were defined within 72 muscles. The standardized uptake value (SUV) of FDG by muscle tissue per unit volume was calculated, and the mean SUV of the pitchers was compared with that of a healthy adult control group who did not exercise before the measurements. Statistical analysis was performed using a t-test, and P < 0.05 was considered statistically significant.ResultsWhole-body PET images showed a significant increase in glucose metabolism in the muscle groups of the fingers and toes in both the throwing and non-throwing sides. Additionally, asymmetric increases in glucose metabolism were observed in the muscles of the thigh.ConclusionsThis is the first study to evaluate whole-body muscle metabolism during pitching using PET-CT. Our findings would be useful in determining the training required for pitchers, and can be further applied to other sporting activities that involve throwing.

The role of striated muscle Pik3r1 in glucose and protein metabolism following chronic glucocorticoid exposure

Chronic glucocorticoid exposure causes insulin resistance and muscle atrophy in skeletal muscle. We previously identified phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1) as a primary target gene of skeletal muscle glucocorticoid receptors involved in the glucocorticoid-mediated suppression of insulin action. However, the in vivo functions of Pik3r1 remain unclear. Here, we generated striated muscle-specific Pik3r1 knockout (MKO) mice and treated them with a dexamethasone (DEX), a synthetic glucocorticoid. Treating wildtype (WT) mice with DEX attenuated insulin activated Akt activity in liver, epididymal white adipose tissue, and gastrocnemius (GA) muscle. This DEX effect was diminished in GA muscle of MKO mice, therefore, resulting in improved glucose and insulin tolerance in DEX-treated MKO mice. Stable isotope labeling techniques revealed that in WT mice, DEX treatment decreased protein fractional synthesis rates in GA muscle. Furthermore, histology showed that in WT mice, DEX treatment reduced GA myotube diameters. In MKO mice, myotube diameters were smaller than in WT mice, and there were more fast oxidative fibers. Importantly, DEX failed to further reduce myotube diameters. Pik3r1 knockout also decreased basal protein synthesis rate (likely caused by lower 4E-BP1 phosphorylation at Thr37/Thr46) and curbed the ability of DEX to attenuate protein synthesis rate. Finally, the ability of DEX to inhibit eIF2α phosphorylation and insulin-induced 4E-BP1 phosphorylation was reduced in MKO mice. Taken together, these results demonstrate the role of Pik3r1 in glucocorticoid-mediated effects on glucose and protein metabolism in skeletal muscle.

Insulin-Regulated Aminopeptidase Inhibition Ameliorates Metabolism in Obese Zucker Rats.

The aim of our study was to determine the influence of inhibition of insulin-regulated aminopeptidase/oxytocinase (IRAP) on glucose tolerance and metabolism of skeletal muscle and visceral adipose tissue in obese Zucker rats. Obese Zucker rats administered with IRAP inhibitor–HFI-419 at a dose of 29 μg/100 g BW/day by osmotic minipumps implanted subcutaneously for 2 weeks. Two-hour intraperitoneal glucose tolerance test (ipGTT) was performed in fasting rats. Plasma oxytocin levels were measured by enzyme immunoassay after plasma extraction. In the musculus quadriceps and epididymal adipose tissue, the expression of factors affecting tissue oxidative status and metabolism was determined by real-time qPCR and/or Western blot analysys. The plasma and tissue enzymatic activities were determined by colorimetric or fluorometric method. Circulated oxytocin levels in obese animals strongly tended to increase after HFI-419 administration. This was accompanied by significantly improved glucose utilization during ipGTT and decreased area under the curve (AUC) for glucose. In skeletal muscle IRAP inhibitor treatment up-regulated enzymes of antioxidant defense system – superoxide dismutase 1 and 2 and improved insulin signal transduction pathway. HFI-419 increased skeletal muscle aminopeptidase A expression and activity and normalized its plasma levels in obese animals. In epididymal adipose tissue, gene expression of markers of inflammation and adipocyte hypertrophy was down-regulated in obese rats after HFI-419 treatment. Our results demonstrate that IRAP inhibition improves whole-body glucose tolerance in insulin-resistant Zucker fatty rats and that this metabolic effect of HFI-419 involves ameliorated redox balance in skeletal muscle.