Glucose Transport In Muscle Research Articles

Skeletal muscle from TBC1D4 p.Arg684Ter variant carriers is severely insulin resistant but exhibits normal metabolic responses during exercise.

In the Greenlandic Inuit population, 4% are homozygous carriers of a genetic nonsense TBC1D4 p.Arg684Ter variant leading to loss of the muscle-specific isoform of TBC1D4 and an approximately tenfold increased risk of type 2 diabetes1. Here we show the metabolic consequences of this variant in four female and four male homozygous carriers and matched controls. An extended glucose tolerance test reveals prolonged hyperglycaemia followed by reactive hypoglycaemia in the carriers. Whole-body glucose disposal is impaired during euglycaemic-hyperinsulinaemic clamp conditions and associates with severe insulin resistance in skeletal muscle only. Notably, a marked reduction in muscle glucose transporter GLUT4 and associated proteins is observed. While metabolic regulation during exercise remains normal, the insulin-sensitizing effect of a single exercise bout is compromised. Thus, loss of the muscle-specific isoform of TBC1D4 causes severe skeletal muscle insulin resistance without baseline hyperinsulinaemia. However, physical activity can ameliorate this condition. These observations offer avenues for personalized interventions and targeted preventive strategies.

Thermotherapy has Sexually Dimorphic Responses in APP/PS1 Mice.

A thermoregulatory decline occurs with age due to changes in muscle mass, vasoconstriction, and metabolism that lowers core body temperature (Tc). Although lower Tc is a biomarker of successful aging, we have previously shown this worsens cognitive performance in the APP/PS1 mouse model of Alzheimer's disease (AD) [1]. We hypothesized that elevating Tc with thermotherapy would improve metabolism and cognition in APP/PS1 mice. From 6-12 months of age, male and female APP/PS1 and C57BL/6 mice were chronically housed at 23 or 30°C. At 12 months of age, mice were assayed for insulin sensitivity, glucose tolerance, and spatial cognition. Plasma, hippocampal, and peripheral (adipose, hepatic, and skeletal muscle) samples were procured postmortem and tissue-specific markers of amyloid accumulation, metabolism, and inflammation were assayed. Chronic 30°C exposure increased Tc in all groups except female APP/PS1 mice. All mice receiving thermotherapy had either improved glucose tolerance or insulin sensitivity, but the underlying processes responsible for these effects varied across sexes. In males, glucose regulation was influenced predominantly by hormonal signaling in plasma and skeletal muscle glucose transporter 4 expression, whereas in females, this was modulated at the tissue level. Thermotherapy improved spatial navigation in male C57BL/6 and APP/PS1 mice, with the later attributed to reduced hippocampal soluble amyloid-β (Aβ)42. Female APP/PS1 mice exhibited worse spatial memory recall after chronic thermotherapy. Together, the data highlights the metabolic benefits of passive thermotherapy, but future studies are needed to determine therapeutic benefits for those with AD.

Chronic Administration of Exogenous Lactate Increases Energy Expenditure during Exercise through Activation of Skeletal Muscle Energy Utilization Capacity in Mice.

We compared the effects of chronic exogenous lactate and exercise training, which influence energy substrate utilization and body composition improvements at rest and during exercise, and investigated the availability of lactate as a metabolic regulator. The mice were divided into four groups: CON (sedentary + saline), LAC (sedentary + lactate), EXE (exercise + saline), and EXLA (exercise + lactate). The total experimental period was set at 4 weeks, the training intensity was set at 60-70% VO2max, and each exercise group was administered a solution immediately after exercise. Changes in the energy substrate utilization at rest and during exercise, the protein levels related to energy substrate utilization in skeletal muscles, and the body composition were measured. Lactate intake and exercise increased carbohydrate oxidation as a substrate during exercise, leading to an increased energy expenditure and increased protein levels of citrate synthase and malate dehydrogenase 2, key factors in the TCA(tricarboxylic acid) cycle of skeletal muscle. Exercise, but not lactate intake, induced the upregulation of the skeletal muscle glucose transport factor 4 and a reduction in body fat. Hence, chronic lactate administration, as a metabolic regulator, influenced energy substrate utilization by the skeletal muscle and increased energy expenditure during exercise through the activation of carbohydrate metabolism-related factors. Therefore, exogenous lactate holds potential as a metabolic regulator.

Intervening effects of progesterone combined with estradiol on streptozotocin-induced diabetes in ovariectomized mice and the underlying mechanisms

Background: Estrogen and progesterone are closely related to the occurrence of diabetes, and the progestogenic and estrogenic effects in the development of diabetes are related to their blood levels and the organism state, and it is not clear what effect their combination will be. The present study was to investigate the interaction between estrogen and progesterone in the development of diabetes mellitus. Methods: A model of type 1 diabetes mellitus（T1DM）was established in ovariectomized (OVX) mice by intraperitoneal injection of streptozotocin (STZ), and the levels of plasma glucose, insulin, C-peptide, progesterone, and estradiol, the changes of islet cells, the expressions of glucose transporter 4 (GLUT4), Glucokinase (Gck), Glucose-6-phosphatase (G-6-P) and phosphoenolpyruvate carboxylase (PCK) were detected after chronically injected different doses of progesterone and 17β-estradiol subcutaneously for 4 weeks. Results: Progesterone and 17β-estradiol could delay the occurrence of T1DM induced by STZ in ovariectomized mice, but there was no dose-response relationship; progesterone (2mg/kg) and 17β-estradiol (0.1mg/kg) injected separately or jointly could make the plasma concentration of estradiol and progesterone reaches the physiological dose range, which markedly inhibited the increase of the blood glucose induced by STZ, improved the glucose tolerance, protected islet cells, promoted C-peptide and insulin secretion, up-regulated skeletal muscle GLUT4 and liver Gck expressions, but significantly down-regulated the expressions of liver PCK and G-6-P mRNA. Conclusions: The physiological dose of progesterone combined with estradiol has certain synergistic effects in delaying the occurrence of diabetes, the mechanisms are probably related to the protection of islet cells, the promotion of insulin release, skeletal muscle glucose transport, and liver glucose metabolism.

Enhancing Muscle Intracellular Ca2+ Homeostasis and Glucose Uptake: Passive Pulsatile Shear Stress Treatment in Type 2 Diabetes.

Type 2 diabetes mellitus (T2D) is a significant global public health problem that has seen a substantial increase in the number of affected individuals in recent decades. In a murine model of T2D (db/db), we found several abnormalities, including aberrant intracellular calcium concentration ([Ca2+]i), decreased glucose transport, increased production of reactive oxygen species (ROS), elevated levels of pro-inflammatory interleukins and creatine phosphokinase (CK), and muscle weakness. Previously, we demonstrated that passive pulsatile shear stress, generated by sinusoidal (headward-forward) motion, using a motion platform that provides periodic acceleration of the whole body in the Z plane (pGz), induces the synthesis of nitric oxide (NO) mediated by constitutive nitric oxide synthase (eNOS and nNOS). We investigated the effect of pGz on db/db a rodent model of T2D. The treatment of db/db mice with pGz resulted in several beneficial effects. It reduced [Ca2+]i overload; enhanced muscle glucose transport; and decreased ROS levels, interleukins, and CK. Furthermore, pGz treatment increased the expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS), and neuronal nitric oxide synthase (nNOS); reduced inducible nitric oxide synthase (iNOS); and improved muscle strength. The cytoprotective effects of pGz appear to be mediated by NO, since pretreatment with L-NAME, a nonspecific NOS inhibitor, abolished the effects of pGz on [Ca2+]i and ROS production. Our findings suggest that a non-pharmacological strategy such as pGz has therapeutic potential as an adjunct treatment to T2D.

The Effect of Walking Exercise Intervention on Blood Glucose Levels in Type 2 Diabetes Mellitus Patients in the Work Area of the Dempar Kutai Barat Health Center

Introduction: In 2021 people with Diabetes Mellitus at Work Area Dempar Public Health Center Dempar are still high, while patient visits to health services are still relatively low. Walking exercise is drug therapy and a healthy diet. Walking exercise performed 3-4 times a week with moderate intensity can rapidly increase the glucose transporter in skeletal muscle, so that fatty acid oxidation and glucose absorption will be accelerated. Objective: This study aims to identify the effect of programmed walking exercise on blood glucose levels in patients with type 2 Diabetes Mellitus. Method: This type of experimental research uses a quasi-experimental design without control with purposive sampling involving 11 respondents. Analysis of the data using the Reaped Measured ANOVA test. Result and Discussion: walking exercise 3 times a week there was a decrease in the average of the first week to the fourth week of 124 g/dl, p-value 0.000 (<0.05). Conclusion: that there is an effect of walking exercise on blood sugar of DM patients in the area of ??Dempar Public Health Center.

Energy (and Reactive Oxygen Species Generation) Saving Distribution of Mitochondria for the Activation of ATP Production in Skeletal Muscle.

Exercise produces oxidants from a variety of intracellular sources, including NADPH oxidases (NOX) and mitochondria. Exercise-derived reactive oxygen species (ROS) are beneficial, and the amount and location of these ROS is important to avoid muscle damage associated with oxidative stress. We discuss here some of the evidence that involves ROS production associated with skeletal muscle contraction and the potential oxidative stress associated with muscle contraction. We also discuss the potential role of H2O2 produced after NOX activation in the regulation of glucose transport in skeletal muscle. Finally, we propose a model based on evidence for the role of different populations of mitochondria in skeletal muscle in the regulation of ATP production upon exercise. The subsarcolemmal population of mitochondria has the enzymatic and metabolic components to establish a high mitochondrial membrane potential when fissioned at rest but lacks the capacity to produce ATP. Calcium entry into the mitochondria will further increase the metabolic input. Upon exercise, subsarcolemmal mitochondria will fuse to intermyofibrillar mitochondria and will transfer the mitochondria membrane potential to them. These mitochondria are rich in ATP synthase and will subsequentially produce the ATP needed for muscle contraction in long-term exercise. These events will optimize energy use and minimize mitochondria ROS production.

Phosphorylation of the N-terminus of Syntaxin-16 controls interaction with mVps45 and GLUT4 trafficking in adipocytes.

The ability of insulin to stimulate glucose transport in muscle and fat cells is mediated by the regulated delivery of intracellular vesicles containing glucose transporter-4 (GLUT4) to the plasma membrane, a process known to be defective in disease such as Type 2 diabetes. In the absence of insulin, GLUT4 is sequestered in tubules and vesicles within the cytosol, collectively known as the GLUT4 storage compartment. A subset of these vesicles, known as the 'insulin responsive vesicles' are selectively delivered to the cell surface in response to insulin. We have previously identified Syntaxin16 (Sx16) and its cognate Sec1/Munc18 protein family member mVps45 as key regulatory proteins involved in the delivery of GLUT4 into insulin responsive vesicles. Here we show that mutation of a key residue within the Sx16 N-terminus involved in mVps45 binding, and the mutation of the Sx16 binding site in mVps45 both perturb GLUT4 sorting, consistent with an important role of the interaction of these two proteins in GLUT4 trafficking. We identify Threonine-7 (T7) as a site of phosphorylation of Sx16 in vitro. Mutation of T7 to D impairs Sx16 binding to mVps45 in vitro and overexpression of T7D significantly impaired insulin-stimulated glucose transport in adipocytes. We show that both AMP-activated protein kinase (AMPK) and its relative SIK2 phosphorylate this site. Our data suggest that Sx16 T7 is a potentially important regulatory site for GLUT4 trafficking in adipocytes.

PKCα Isoform Inhibits Insulin Signaling and Aggravates Neuronal Insulin Resistance.

Overexpression of PKCα has been linked to inhibit insulin signaling disrupting IRS-1 and Akt phosphorylations in skeletal muscle. PKCα inhibits IRS-1 and Akt phosphorylations, but not required for insulin-stimulated glucose transport in skeletal muscles. Inhibition of PKCα increased whereas in some studies decreased GLUT-4 levels at the plasma membrane in skeletal muscles and adipocytes. Controversial studies have reported opposite expression pattern of PKCα expression in insulin-resistant skeletal muscles. These findings indicate that the role of PKCα on insulin signaling is controversial and could be tissue specific. Evidently, studies are required to decipher the role of PKCα in regulating insulin signaling and preferably in other cellular systems. Utilizing neuronal cells, like Neuro-2a, SHSY-5Y and insulin-resistant diabetic mice brain tissues; we have demonstrated that PKCα inhibits insulin signaling, through IRS-Akt pathway in PP2A-dependent mechanism by an AS160-independent route involving 14-3-3ζ. Inhibition and silencing of PKCα improves insulin sensitivity by increasing GLUT-4 translocation to the plasma membrane and glucose uptake. PKCα regulates GSK3 isoforms in an opposite manner in insulin-sensitive and in insulin-resistant condition. Higher activity of PKCα aggravates insulin-resistant neuronal diabetic condition through GSK3β but not GSK3α. Our results mechanistically explored the contribution of PKCα in regulating neuronal insulin resistance and diabetes, which opens up new avenues in dealing with metabolic disorders and neurodegenerative disorders.

1622-P: Complex Mechanisms Underlie the Antidiabetic Effect of Tempol in Experimentally Induced Diabetes Mellitus

Diabetes mellitus (DM) is a vastly growing worldwide health problem which imposes public health, social, as well as economic burden. Multifactorial and complicated pathophysiological pathways may underlie DM. Attention has been given for the search of polymodal therapeutic molecules. Herein, we tested the capacity of tempol, a known superoxide dismutase-mimetic in the treatment of experimentally induced DM. Thirty male Wistar rats weighing 150-200 g were equally divided into: 1- Control group (rats received a single intra-peritoneal injection of citrate buffer for 4 weeks), 2- Untreated diabetic group, and 3- Tempol treated diabetic group. At the end of the study blood samples were collected for the measurement of fasting blood glucose, fasting blood insulin, liver function, kidney function, oxidative stress markers, and inflammatory markers. Pancreas, skeletal muscles, and liver were removed for histopathological, immunohistochemical and RT-PCR studies. Treatment with tempol significantly improved glycemic status, insulin secretion, sensitivity and reserve. Tempol preserved both liver and kidney functions. Tempol also significantly enhanced energy status, and countered structural changes, inflammation, and apoptosis of pancreatic tissue. Tempol significantly upregulated pancreatic AMPK, and skeletal muscle and hepatic glucose transporters. Interestingly, tempol demonstrated an endogenous stem cells recruitment capacity. In conclusion, tempol exhibited a potential capacity to counter the complexity of the underlying mechanisms in DM. Disclosure Y.Naguib: None.

A very high-carbohydrate diet differentially affects whole-body glucose tolerance and hepatic insulin resistance in rats

ObjectivesThis study was performed to assess the effects of long-term intake of a very high carbohydrate (VHCHO) diet (76% of total energy from carbohydrate [CHO]) on whole-body glucose tolerance and hepatic insulin resistance. Methods and MaterialsMale Sprague Dawley rats were fed either a control high-CHO diet (59% total energy from CHO; n = 8) or a VHCHO diet (76% total energy from CHO; n = 8) for 17 wk. At 4, 8, 12, and 16 wk of the dietary intervention, oral glucose tolerance test and homeostasis model assessment of insulin resistance (HOMA-IR) measurements were taken to assess whole-body glucose tolerance and hepatic insulin resistance, respectively. The triacylglycerol concentration in the liver was measured at the end of the 17-wk intervention period. ResultsThe VHCHO diet group showed significantly higher muscle glucose transporter 4 content and a smaller area under the curve for plasma glucose, but not insulin, in the oral glucose tolerance test compared with the control group. On the other hand, the VHCHO diet group had a significantly higher hepatic triacylglycerol concentration and HOMA-IR measurement compared with the control group. The hepatic triacylglycerol concentration was significantly and positively correlated with HOMA-IR. ConclusionsThe results of the present study suggest that long-term intake of a VHCHO diet exerts differential effects on whole-body glucose tolerance and hepatic insulin resistance.

The specific mitochondrial unfolded protein response in fast- and slow-twitch muscles of high-fat diet-induced insulin-resistant rats.

Skeletal muscle insulin resistance (IR) plays an important role in the pathogenesis of type 2 diabetes mellitus. Skeletal muscle is a heterogeneous tissue composed of different muscle fiber types that contribute distinctly to IR development. Glucose transport shows more protection in slow-twitch muscles than in fast-twitch muscles during IR development, while the mechanisms involved remain unclear. Therefore, we investigated the role of the mitochondrial unfolded protein response (UPRmt) in the distinct resistance of two types of muscle in IR. Male Wistar rats were divided into high-fat diet (HFD) feeding and control groups. We measured glucose transport, mitochondrial respiration, UPRmt and histone methylation modification of UPRmt-related proteins to examine the UPRmt in the slow fiber-enriched soleus (Sol) and fast fiber-enriched tibialis anterior (TA) under HFD conditions. Our results indicate that 18 weeks of HFD can cause systemic IR, while the disturbance of Glut4-dependent glucose transport only occurred in fast-twitch muscle. The expression levels of UPRmt markers, including ATF5, HSP60 and ClpP, and the UPRmt-related mitokine MOTS-c were significantly higher in slow-twitch muscle than in fast-twitch muscle under HFD conditions. Mitochondrial respiratory function is maintained only in slow-twitch muscle. Additionally, in the Sol, histone methylation at the ATF5 promoter region was significantly higher than that in the TA after HFD feeding. The expression of proteins involved in glucose transport in slow-twitch muscle remains almost unaltered after HFD intervention, whereas a significant decline of these proteins was observed in fast-twitch muscle. Specific activation of the UPRmt in slow-twitch muscle, accompanied by higher mitochondrial respiratory function and MOTS-c expression, may contribute to the higher resistance to HFD in slow-twitch muscle. Notably, the different histone modifications of UPRmt regulators may underlie the specific activation of the UPRmt in different muscle types. However, future work applying genetic or pharmacological approaches should further uncover the relationship between the UPRmt and insulin resistance.

Urtica dioica (Gazaneh) distillate restores glucose metabolism in diabetic rats.

Diabetes has become an important health problem in the world. Natural agents, with antidiabetic property, are potential candidates for improving diabetes. Urtica Dioica Distillate (UDD) or Araghe Gazaneh is widely used for the treatment of diabetes as per traditional medicine. Despite the tremendous use of UDD as an antidiabetic compound in folk medicine, the antidiabetic effects of UDD has been neglected by medical scientists. In this study, we aimed to evaluate the effects of UDD on the glucose metabolism in diabetic rats. A total of 24 male rats were divided equally into four groups, two treatment and two control groups, each containing normal or Streptozotocin (STZ)-induced diabetic rats. During 4 weeks, control and treatment rats received water or UDD, respectively. Fasting blood sugar (FBS), HbA1c, serum creatinine, blood urea nitrogen, and specific activities of hepatic enzymes including glucokinase (GK), hexokinase (HK), glucose-6-phosphate dehydrogenase (G6PD), and muscle glucose transporter type 4 (GLUT4) and liver phosphoenolpyruvate carboxykinase (PEPCK) mRNA levels were measured. FBS and HbA1c increased in diabetic groups. Treatment with UDD significantly lowered FBS and prevented weight loss. Decreased FBS level was associated with higher activity levels of GK and HK in UDD-treated diabetic rats. G6PD-specific activity decreased in diabetic control rats compared to nondiabetic ones, but UDD treatment improved it to the normal levels. A significant decrease in the expression level of GLUT4 was observed in diabetic control rats compared to nondiabetic ones, but UDD increased it to the normal levels. These findings suggest that UDD might exert therapeutic effects against diabetes by improving glucose metabolism and can be used as an alternative or complementary medicine for the treatment of diabetic patients.

Liver-Secreted Hexosaminidase A Regulates Insulin-Like Growth Factor Signaling and Glucose Transport in Skeletal Muscle.

Nonalcoholic fatty liver disease (NAFLD) and impaired glycemic control are closely linked; however, the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved. The high secretory capacity of the liver and impairments in protein secretion in NAFLD suggest that endocrine changes in the liver are likely to contribute to glycemic defects. We identify hexosaminidase A (HEXA) as an NAFLD-induced hepatokine in both mice and humans. HEXA regulates sphingolipid metabolism, converting GM2 to GM3 gangliosides-sphingolipids that are primarily localized to cell-surface lipid rafts. Using recombinant murine HEXA protein, an enzymatically inactive HEXA(R178H) mutant, or adeno-associated virus vectors to induce hepatocyte-specific overexpression of HEXA, we show that HEXA improves blood glucose control by increasing skeletal muscle glucose uptake in mouse models of insulin resistance and type 2 diabetes, with these effects being dependent on HEXA's enzymatic action. Mechanistically, HEXA remodels muscle lipid raft ganglioside composition, thereby increasing IGF-1 signaling and GLUT4 localization to the cell surface. Disrupting lipid rafts reverses these HEXA-mediated effects. In this study, we identify a pathway for intertissue communication between liver and skeletal muscle in the regulation of systemic glycemic control.

Muscle-Specific Ablation of Glucose Transporter 1 (GLUT1) Does Not Impair Basal or Overload-Stimulated Skeletal Muscle Glucose Uptake.

Glucose transporter 1 (GLUT1) is believed to solely mediate basal (insulin-independent) glucose uptake in skeletal muscle; yet recent work has demonstrated that mechanical overload, a model of resistance exercise training, increases muscle GLUT1 levels. The primary objective of this study was to determine if GLUT1 is necessary for basal or overload-stimulated muscle glucose uptake. Muscle-specific GLUT1 knockout (mGLUT1KO) mice were generated and examined for changes in body weight, body composition, metabolism, systemic glucose regulation, muscle glucose transporters, and muscle [3H]-2-deoxyglucose uptake ± the GLUT1 inhibitor BAY-876. [3H]-hexose uptake ± BAY-876 was also examined in HEK293 cells-expressing GLUT1-6 or GLUT10. mGLUT1KO mice exhibited no impairments in body weight, lean mass, whole body metabolism, glucose tolerance, basal or overload-stimulated muscle glucose uptake. There was no compensation by the insulin-responsive GLUT4. In mGLUT1KO mouse muscles, overload stimulated higher expression of mechanosensitive GLUT6, but not GLUT3 or GLUT10. In control and mGLUT1KO mouse muscles, 0.05 µM BAY-876 impaired overload-stimulated, but not basal glucose uptake. In the GLUT-HEK293 cells, BAY-876 inhibited glucose uptake via GLUT1, GLUT3, GLUT4, GLUT6, and GLUT10. Collectively, these findings demonstrate that GLUT1 does not mediate basal muscle glucose uptake and suggest that a novel glucose transport mechanism mediates overload-stimulated glucose uptake.

P62/Sqstm1 rescue in muscle retards the progression of steatohepatitis in p62/Sqstm1-null mice fed a high-fat diet.

Introduction: Obesity is a risk factor for many diseases because it leads to a reduction in skeletal muscle mass and promotes insulin resistance. p62/Sqstm1-knockout mice are a model of metabolic syndrome; show obesity, insulin resistance, and non-alcoholic fatty liver (NAFL); and develop non-alcoholic steatohepatitis (NASH) in response to the feeding of a high-fat diet (HFD). These phenotypes suggest that muscle p62 may prevent obesity-induced muscle dysfunction. In the present study, we aimed to determine the effects of muscle p62 on skeletal muscle mass, muscle strength, insulin resistance, and NASH pathology. Methods: We generated muscle-specific p62 gene rescue mice (p62-mRes), which express p62 only in muscle and were derived from p62-knock out mice (p62 KIKI ) using the cre/loxp system. p62 KIKI and p62-mRes mice were fed an HFD for 20 weeks and their phenotypes were compared. Results: HFD-feeding caused severe obesity in both p62 KIKI and p62-mRes mice, but there was no effect of muscle p62 on body mass. Limb skeletal muscle mass, grip strength, and the cross-sectional area of muscle fibers were higher in p62-mRes mice than in p62 KIKI . The glucose tolerance and insulin sensitivity of the p62-mRes mice were also superior. The protein expression of mechanistic target of rapamycin, which promotes muscle protein synthesis, and GLUT4, a glucose transporter in skeletal muscle, were higher in the p62-mRes mice. p62 KIKI mice developed severe NASH when fed an HFD, but the progression of NASH was retarded by p62 gene rescue in muscle, and the expression of Tgf-β1, which encodes a factor that promotes hepatic fibrosis, was reduced. Conclusion: Rescue of muscle-specific p62 in the whole-body p62 knock-out mice ameliorates the insulin resistance and retards the progression of NASH caused by systemic p62 ablation.

Chemotherapeutic drug screening in 3D-Bioengineered human myobundles provides insight into taxane-induced myotoxicities

SummaryTwo prominent frontline breast cancer (BC) chemotherapies commonly used in combination, doxorubicin (DOX) and docetaxel (TAX), are associated with long-lasting cardiometabolic and musculoskeletal side effects. Whereas DOX has been linked to mitochondrial dysfunction, mechanisms underlying TAX-induced myotoxicities remain uncertain. Here, the metabolic and functional consequences of TAX ± DOX were investigated using a 3D-bioengineered model of adult human muscle and a drug dosing regimen designed to resemble in vivo pharmacokinetics. DOX potently reduced mitochondrial respiratory capacity, 3D-myobundle size, and contractile force, whereas TAX-induced acetylation and remodeling of the microtubule network led to perturbations in glucose uptake, mitochondrial respiratory sensitivity, and kinetics of fatigue, without compromising tetanic force generation. These findings suggest TAX-induced remodeling of the microtubule network disrupts glucose transport and respiratory control in skeletal muscle and thereby have important clinical implications related to the cardiometabolic health and quality of life of BC patients and survivors.

Skeletal-Muscle-Specific Overexpression of Chrono Leads to Disruption of Glucose Metabolism and Exercise Capacity.

Disruption of circadian rhythms is related to disorders of glucose metabolism, and the molecular clock also exists in skeletal muscle. The ChIP-derived repressor of network oscillator (Chrono) and brain and muscle ARNT-like 1 (Bmal1) are core circadian components. Chrono is considered to be the repressor of Bmal1, and the Chrono–Bmal1 pathway is important in regulating the circadian rhythm; it has been speculated that this pathway could be a new mechanism for regulating glucose metabolism. The purpose of this study was to investigate the effects of Chrono on glucose metabolism in skeletal muscle and exercise capacity by using mice with skeletal-muscle-specific overexpression of Chrono (Chrono TG) and wild-type (WT) mice as the animal models. The results of this cross-sectional study indicated that the Chrono TG mice had an impaired glucose tolerance, lower exercise capacity, and higher levels of nonfasted blood glucose and glycogen content in skeletal muscle compared to WT mice. In addition, the Chrono TG mice also showed a significant increase in the amount of Chrono bound to Bmal1 according to a co-IP analysis; a remarkable decrease in mRNA expression of Tbc1d1, Glut4, Hk2, Pfkm, Pdp1, Gbe1, and Phka1, as well as in activity of Hk and protein expression of Ldhb; but higher mRNA expression of Pdk4 and protein expression of Ldha compared with those of WT mice. These data suggested the skeletal-muscle-specific overexpression of Chrono led to a greater amount of Chrono bound to Bmal1, which then could affect the glucose transporter, glucose oxidation, and glycogen utilization in skeletal muscle, as well as exercise capacity.

EFR3 and phosphatidylinositol 4-kinase IIIα regulate insulin-stimulated glucose transport and GLUT4 dispersal in 3T3-L1 adipocytes.

Insulin stimulates glucose transport in muscle and adipocytes. This is achieved by regulated delivery of intracellular glucose transporter (GLUT4)-containing vesicles to the plasma membrane where they dock and fuse, resulting in increased cell surface GLUT4 levels. Recent work identified a potential further regulatory step, in which insulin increases the dispersal of GLUT4 in the plasma membrane away from the sites of vesicle fusion. EFR3 is a scaffold protein that facilitates localization of phosphatidylinositol 4-kinase type IIIα to the cell surface. Here we show that knockdown of EFR3 or phosphatidylinositol 4-kinase type IIIα impairs insulin-stimulated glucose transport in adipocytes. Using direct stochastic reconstruction microscopy, we also show that EFR3 knockdown impairs insulin stimulated GLUT4 dispersal in the plasma membrane. We propose that EFR3 plays a previously unidentified role in controlling insulin-stimulated glucose transport by facilitating dispersal of GLUT4 within the plasma membrane.

Modeling the measurement bias in interstitial glucose concentrations derived from microdialysis in skeletal muscle.

Muscle tissue utilizes glucose as a fuel during exercise and stores glucose in form of glycogen during rest. The associated glucose transport includes delivery of glucose from blood plasma into the interstitial space and subsequent, GLUT‐4 facilitated diffusion into muscle cells. The extent to which the vascular endothelium acts as a barrier to glucose transport, however, remains debated. While accurate measurements of interstitial glucose concentration (IGC) are key to resolve this debate, these are also challenging as removal of interstitial fluid may perturb glucose transport and therefore bias IGC measurements. We developed a three‐compartment model to infer IGC in skeletal muscle from its local metabolism and blood flow. The model predicts that IGC remains within 5% of that of blood plasma during resting conditions but decreases more as metabolism increases. Next, we determined how microdialysis protocols affect IGC. Our model analysis suggests that microdialysis‐based IGC measurements underestimate true values. Notably, reported increases in muscle capillary permeability surface area product (PS) to glucose under the condition of elevated metabolism may owe in part to such measurements bias.Our study demonstrates that microdialysis may be associated with significant measurement bias in the context of muscle IGC assessment. Reappraising literature data with this bias in mind, we find that muscle capillary endothelium may represent less of a barrier to glucose transport in muscle than previously believed. We discuss the impact of glucose removal on the microdialysis relative recovery and means of correcting microdialysis IGC values.