Abnormalities of AMPK Activation and Glucose Uptake in Cultured Skeletal Muscle Cells from Individuals with Chronic Fatigue Syndrome

Background

Post exertional muscle fatigue is a key feature in Chronic Fatigue Syndrome (CFS). Abnormalities of skeletal muscle function have been identified in some but not all patients with CFS. To try to limit potential confounders that might contribute to this clinical heterogeneity, we developed a novel in vitro system that allows comparison of AMP kinase (AMPK) activation and metabolic responses to exercise in cultured skeletal muscle cells from CFS patients and control subjects.

Methods

Skeletal muscle cell cultures were established from 10 subjects with CFS and 7 age-matched controls, subjected to electrical pulse stimulation (EPS) for up to 24h and examined for changes associated with exercise.

Results

In the basal state, CFS cultures showed increased myogenin expression but decreased IL6 secretion during differentiation compared with control cultures. Control cultures subjected to 16h EPS showed a significant increase in both AMPK phosphorylation and glucose uptake compared with unstimulated cells. In contrast, CFS cultures showed no increase in AMPK phosphorylation or glucose uptake after 16h EPS. However, glucose uptake remained responsive to insulin in the CFS cells pointing to an exercise-related defect. IL6 secretion in response to EPS was significantly reduced in CFS compared with control cultures at all time points measured.

Conclusion

EPS is an effective model for eliciting muscle contraction and the metabolic changes associated with exercise in cultured skeletal muscle cells. We found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6. The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets.     

Evidence for ACTN3 as a Speed Gene in Isolated Human Muscle Fibers

Purpose

To examine the effect of α-actinin-3 deficiency due to homozygosity for the ACTN3 577X-allele on contractile and morphological properties of fast muscle fibers in non-athletic young men.

Methods

A biopsy was taken from the vastus lateralis of 4 RR and 4 XX individuals to test for differences in morphologic and contractile properties of single muscle fibers. The cross-sectional area of the fiber and muscle fiber composition was determined using standard immunohistochemistry analyses. Skinned single muscle fibers were subjected to active tests to determine peak normalized force (P₀), maximal unloading velocity (V₀) and peak power. A passive stretch test was performed to calculate Young’s Modulus and hysteresis to assess fiber visco-elasticity.

Results

No differences were found in muscle fiber composition. The cross-sectional area of type II_a and II_x fibers was larger in RR compared to XX individuals (P<0.001). P₀ was similar in both groups over all fiber types. A higher V₀ was observed in type II_a fibers of RR genotypes (P<0.001) but not in type I fibers. The visco-elasticity as determined by Young’s Modulus and hysteresis was unaffected by fiber type or genotype.

Conclusion

The greater V₀ and the larger fast fiber CSA in RR compared to XX genotypes likely contribute to enhanced whole muscle performance during high velocity contractions.     

Nox4 Is Dispensable for Exercise Induced Muscle Fibre Switch

Introduction

By producing H₂O₂, the NADPH oxidase Nox4 is involved in differentiation of mesenchymal cells. Exercise alters the composition of slow and fast twitch fibres in skeletal. Here we hypothesized that Nox4 contributes to exercise-induced adaptation such as changes in muscle metabolism or muscle fibre specification and studied this in wildtype and Nox4-/- mice.

Results

Exercise, as induced by voluntary running in a running wheel or forced running on a treadmill induced a switch from fast twitch to intermediate fibres. However the induced muscle fibre switch was similar between Nox4-/- and wildtype mice. The same held true for exercise-induced expression of PGC1α or AMPK activation. Both are increased in response to exercise, but with no difference was observed between wildtype and Nox4-/- mice.

Conclusion

Thus, exercise-induced muscle fibre switch is Nox4-independent.     

MicroRNAs as Biomarkers for Acute Atrial Remodeling in Marathon Runners (The miRathon Study – A Sub-Study of the Munich Marathon Study)

Introduction

Physical activity is beneficial for individual health, but endurance sport is associated with the development of arrhythmias like atrial fibrillation. The underlying mechanisms leading to this increased risk are still not fully understood. MicroRNAs are important mediators of proarrhythmogenic remodeling and have potential value as biomarkers in cardiovascular diseases. Therefore, the objective of our study was to determine the value of circulating microRNAs as potential biomarkers for atrial remodeling in marathon runners (miRathon study).

Methods

30 marathon runners were recruited into our study and were divided into two age-matched groups depending on the training status: elite (ER, ≥55 km/week, n = 15) and non-elite runners (NER, ≤40 km/week, n = 15). All runners participated in a 10 week training program before the marathon. MiRNA plasma levels were measured at 4 time points: at baseline (V1), after a 10 week training period (V2), immediately after the marathon (V3) and 24h later (V4). Additionally, we obtained clinical data including serum chemistry and echocardiography at each time point.

Results

MiRNA plasma levels were similar in both groups over time with more pronounced changes in ER. After the marathon miR-30a plasma levels increased significantly in both groups. MiR-1 and miR-133a plasma levels also increased but showed significant changes in ER only. 24h after the marathon plasma levels returned to baseline. MiR-26a decreased significantly after the marathon in elite runners only and miR-29b showed a non-significant decrease over time in both groups. In ER miRNA plasma levels showed a significant correlation with LA diameter, in NER miRNA plasma levels did not correlate with echocardiographic parameters.

Conclusion

MiRNAs were differentially expressed in the plasma of marathon runners with more pronounced changes in ER. Plasma levels in ER correlate with left atrial diameter suggesting that circulating miRNAs could potentially serve as biomarkers of atrial remodeling in athletes.     

Influence of ACE I/D Polymorphism on Circulating Levels of Plasminogen Activator Inhibitor 1, D-Dimer,Ultrasensitive C-Reactive Protein and Transforming Growth Factor β1 in Patients Undergoing Hemodialysis

Background

There is substantial evidence that chronic renal and cardiovascular diseases are associated with coagulation disorders, endothelial dysfunction, inflammation and fibrosis. Angiotensin-Converting Enzyme Insertion/Deletion polymorphism (ACE I/D polymorphism) has also be linked to cardiovascular diseases. Therefore, this study aimed to compare plasma levels of ultrassensible C-reactive protein (usCRP), PAI-1, D-dimer and TGF-β1 in patients undergoing HD with different ACE I/D polymorphisms.

Methods

The study was performed in 138 patients at ESRD under hemodialysis therapy for more than six months. The patients were divided into three groups according to the genotype. Genomic DNA was extracted from blood cells (leukocytes). ACE I/D polymorphism was investigated by single polymerase chain reaction (PCR). Plasma levels of D-dimer, PAI-1 and TGF-β1 were measured by enzyme-linked immunosorbent assay (ELISA), and the determination of plasma levels of usCRP was performed by immunonephelometry. Data were analyzed by the software SigmaStat 2.03.

Results

Clinical characteristics were similar in patients with these three ACE I/D polymorphisms, except for interdialytic weight gain. I allele could be associated with higher interdialytic weight gain (P = 0.017). Patients genotyped as DD and as ID had significantly higher levels of PAI-1 than those with II genotype. Other laboratory parameters did not significantly differ among the three subgroups (P = 0.033). Despite not reaching statistical significance, plasma levels of usCRP were higher in patients carrying the D allele.

Conclusion

ACE I/D polymorphisms could be associated with changes in the regulation of sodium, fibrinolytic system, and possibly, inflammation. Our data showed that high levels of PAI-1 are detected when D allele is present, whereas greater interdialytic gain is associated with the presence of I allele. However, further studies with different experimental designs are necessary to elucidate the mechanisms involved in these associations.     

Pulsatile Hyperglycaemia Induces Vascular Oxidative Stress and GLUT 1 Expression More Potently than Sustained Hyperglycaemia in Rats on High Fat Diet

Introduction

Pulsatile hyperglycaemia resulting in oxidative stress may play an important role in the development of macrovascular complications. We investigated the effects of sustained vs. pulsatile hyperglycaemia in insulin resistant rats on markers of oxidative stress, enzyme expression and glucose metabolism in liver and aorta. We hypothesized that liver’s ability to regulate the glucose homeostasis under varying states of hyperglycaemia may indirectly affect oxidative stress status in aorta despite the amount of glucose challenged with.

Methods

Animals were infused with sustained high (SHG), low (SLG), pulsatile (PLG) glucose or saline (VEH) for 96 h. Oxidative stress status and key regulators of glucose metabolism in liver and aorta were investigated.

Results

Similar response in plasma lipid oxidation was observed in PLG as in SHG. Likewise, in aorta, PLG and SHG displayed increased expression of glucose transporter 1 (GLUT1), gp-91^PHOX and super oxide dismutase (SOD), while only the PLG group showed increased accumulation of oxidative stress and oxidised low density lipoprotein (oxLDL) in aorta.

Conclusion

Pulsatile hyperglycaemia induced relatively higher levels of oxidative stress systemically and in aorta in particular than overt sustained hyperglycaemia thus supporting the clinical observations that pulsatile hyperglycaemia is an independent risk factor for diabetes related macrovascular complications.     

Interleukin-2 Receptor and Angiotensin-Converting Enzyme as Markers for Ocular Sarcoidosis

Purpose

To study the impact of soluble IL2 receptor (sIL2R), chest x-ray (CxR), and angiotensin-converting enzyme (ACE) as markers for sarcoidosis in uveitis patients.

Design

Retrospective study.

Methods

Serum concentrations of sIL2R and ACE were measured in patients with active uveitis. Those with elevated sIL2R and /or ACE values were examined for suspected systemic sarcoidosis.

Main Outcome Measure

Our main outcome parameters were the specificity and sensitivity of sIL2R, CxR and ACE in screening for ocular sarcoidosis.

Results

We measured 261 patients with uveitis for sarcoidosis using sIL2R and ACE between January 2008 and November 2011; sarcoidosis was been diagnosed using other tests (e.g. computer tomography, brochoalveolar lavage, biopsy) in 41 of 53 patients with elevated sIL2R values (>639 U/ml) and in one patient with normal sIL2R (582 U/ml). Their mean sIL2R value was 1310 U/ml, extending from 582 to 8659 U/ml. Only 9 patients, however, presented elevated ACE (>82 U/l). Their mean ACE value was 116.4 U/l, ranging from 84.1 to 175.5 U/l. IL2R specificity was 94% with 98% sensitivity. In contrast, ACE had a specificity of 99.5%, but a sensitivity of only 22%; the chest x-ray had a specificity of 100% with 50% sensitivity in detecting sarcoidosis. We observed the entire spectrum of uveitis: sixteen patients suffered from anterior, 8 from intermediate, 16 from posterior, and 2 from panuveitis.

Conclusions

An elevated level of soluble IL2R suggests sarcoidosis with uveitis more convincingly than ACE, making sIL2R a more effective marker parameter for sarcoidosis than ACE or chest x-ray in uveitis patients.     

CMPF Does Not Associate with Impaired Glucose Metabolism in Individuals with Features of Metabolic Syndrome

Objective

3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) is a metabolite produced endogenously from dietary sources of furan fatty acids. The richest source of furan fatty acids in human diet is fish. CMPF was recently shown to be elevated in fasting plasma in individuals with gestational diabetes and type 2 diabetes, and mechanistically high level of CMPF was linked to β cell dysfunction. Here we aimed to study the association between plasma CMPF level and glucose metabolism in persons with impaired glucose metabolism.

Methods

Plasma CMPF concentration was measured from plasma samples of the study participants in an earlier controlled dietary intervention. All of them had impaired glucose metabolism and two other characteristics of the metabolic syndrome. Altogether 106 men and women were randomized into three groups for 12 weeks with different fish consumption (either three fatty fish meals per week, habitual fish consumption or maximum of one fish meal per week). Associations between concentration of CMPF and various glucose metabolism parameters at an oral glucose tolerance test at baseline and at the end of the study were studied.

Results

Fasting plasma CMPF concentration was significantly increased after a 12-week consumption of fatty fish three times per week, but the concentration remained much lower compared to concentrations reported in diabetic patients. Increases of plasma CMPF concentrations mostly due to increased fish consumption were not associated with impaired glucose metabolism in this study. Instead, elevated plasma CMPF concentration was associated with decreased 2-hour insulin concentration in OGTT.

Conclusions

Moderately elevated concentration of CMPF in plasma resulting from increased intake of fish is not harmful to glucose metabolism. Further studies are needed to fully explore the role of CMPF in the pathogenesis of impaired glucose metabolism.

Trial Registration

ClinicalTrials.gov NCT00573781     

Muscle Damage following Maximal Eccentric Knee Extensions in Males and Females

Aim

To investigate whether there is a sex difference in exercise induced muscle damage.

Materials and Method

Vastus Lateralis and patella tendon properties were measured in males and females using ultrasonography. During maximal voluntary eccentric knee extensions (12 reps x 6 sets), Vastus Lateralis fascicle lengthening and maximal voluntary eccentric knee extensions torque were recorded every 10° of knee joint angle (20–90°). Isometric torque, Creatine Kinase and muscle soreness were measured pre, post, 48, 96 and 168 hours post damage as markers of exercise induced muscle damage.

Results

Patella tendon stiffness and Vastus Lateralis fascicle lengthening were significantly higher in males compared to females (p<0.05). There was no sex difference in isometric torque loss and muscle soreness post exercise induced muscle damage (p>0.05). Creatine Kinase levels post exercise induced muscle damage were higher in males compared to females (p<0.05), and remained higher when maximal voluntary eccentric knee extension torque, relative to estimated quadriceps anatomical cross sectional area, was taken as a covariate (p<0.05).

Conclusion

Based on isometric torque loss, there is no sex difference in exercise induced muscle damage. The higher Creatine Kinase in males could not be explained by differences in maximal voluntary eccentric knee extension torque, Vastus Lateralis fascicle lengthening and patella tendon stiffness. Further research is required to understand the significant sex differences in Creatine Kinase levels following exercise induced muscle damage.     

The Effect of Aerobic Exercise on Neuroplasticity within the Motor Cortex following Stroke

Background

Aerobic exercise is associated with enhanced plasticity in the motor cortex of healthy individuals, but the effect of aerobic exercise on neuroplasticity following a stroke is unknown.

Objective

The aim of this study was to compare corticomotoneuronal excitability and neuroplasticity in the upper limb cortical representation following a single session of low intensity lower limb cycling, or a rest control condition.

Methods

We recruited chronic stroke survivors to take part in three experimental conditions in a randomised, cross-over design. Corticomotoneuronal excitability was examined using transcranial magnetic stimulation to elicit motor evoked potentials in the affected first dorsal interosseus muscle. Following baseline measures, participants either cycled on a stationary bike at a low exercise intensity for 30 minutes, or remained resting in a seated position for 30 minutes. Neuroplasticity within the motor cortex was then examined using an intermittent theta burst stimulation (iTBS) paradigm. During the third experimental condition, participants cycled for the 30 minutes but did not receive any iTBS.

Results

Twelve participants completed the study. We found no significant effect of aerobic exercise on corticomotoneuronal excitability when compared to the no exercise condition (P > 0.05 for all group and time comparisons). The use of iTBS did not induce a neuroplastic-like response in the motor cortex with or without the addition of aerobic exercise.

Conclusions

Our results suggest that following a stroke, the brain may be less responsive to non-invasive brain stimulation paradigms that aim to induce short-term reorganisation, and aerobic exercise was unable to induce or improve this response.     

Effects of Exercise Training on Circulating and Skeletal Muscle Renin-Angiotensin System in Chronic Heart Failure Rats

Background

Accumulated evidence shows that the ACE-AngII-AT1 axis of the renin-angiotensin system (RAS) is markedly activated in chronic heart failure (CHF). Recent studies provide information that Angiotensin (Ang)-(1–7), a metabolite of AngII, counteracts the effects of AngII. However, this balance between AngII and Ang-(1–7) is still little understood in CHF. We investigated the effects of exercise training on circulating and skeletal muscle RAS in the ischemic model of CHF.

Methods/Main Results

Male Wistar rats underwent left coronary artery ligation or a Sham operation. They were divided into four groups: 1) Sedentary Sham (Sham-S), 2) exercise-trained Sham (Sham-Ex), sedentary CHF (CHF-S), and exercise-trained CHF (CHF-Ex). Angiotensin concentrations and ACE and ACE2 activity in the circulation and skeletal muscle (soleus and plantaris) were quantified. Skeletal muscle ACE and ACE2 protein expression, and AT1, AT2, and Mas receptor gene expression were also evaluated. CHF reduced ACE2 serum activity. Exercise training restored ACE2 and reduced ACE activity in CHF. Exercise training reduced plasma AngII concentration in both Sham and CHF rats and increased the Ang-(1–7)/AngII ratio in CHF rats. CHF and exercise training did not change skeletal muscle ACE and ACE2 activity and protein expression. CHF increased AngII levels in both soleus and plantaris muscle, and exercise training normalized them. Exercise training increased Ang-(1–7) in the plantaris muscle of CHF rats. The AT1 receptor was only increased in the soleus muscle of CHF rats, and exercise training normalized it. Exercise training increased the expression of the Mas receptor in the soleus muscle of both exercise-trained groups, and normalized it in plantaris muscle.

Conclusions

Exercise training causes a shift in RAS towards the Ang-(1–7)-Mas axis in skeletal muscle, which can be influenced by skeletal muscle metabolic characteristics. The changes in RAS circulation do not necessarily reflect the changes occurring in the RAS of skeletal muscle.     

Glucose Metabolism Disorders,HIV and Antiretroviral Therapy among Tanzanian Adults

Introduction

Millions of HIV-infected Africans are living longer due to long-term antiretroviral therapy (ART), yet little is known about glucose metabolism disorders in this group. We aimed to compare the prevalence of glucose metabolism disorders among HIV-infected adults on long-term ART to ART-naïve adults and HIV-negative controls, hypothesizing that the odds of glucose metabolism disorders would be 2-fold greater even after adjusting for possible confounders.

Methods

In this cross-sectional study conducted between October 2012 and April 2013, consecutive adults (>18 years) attending an HIV clinic in Tanzania were enrolled in 3 groups: 153 HIV-negative controls, 151 HIV-infected, ART-naïve, and 150 HIV-infected on ART for ≥ 2 years. The primary outcome was the prevalence of glucose metabolism disorders as determined by oral glucose tolerance testing. We compared glucose metabolism disorder prevalence between each HIV group vs. the control group by Fisher’s exact test and used multivariable logistic regression to determine factors associated with glucose metabolism disorders.

Results

HIV-infected adults on ART had a higher prevalence of glucose metabolism disorders (49/150 (32.7%) vs.11/153 (7.2%), p<0.001) and frank diabetes mellitus (27/150 (18.0%) vs. 8/153 (5.2%), p = 0.001) than HIV-negative adults, which remained highly significant even after adjusting for age, gender, adiposity and socioeconomic status (OR = 5.72 (2.78–11.77), p<0.001). Glucose metabolism disorders were significantly associated with higher CD4+ T-cell counts. Awareness of diabetes mellitus was <25%.

Conclusions

HIV-infected adults on long-term ART had 5-fold greater odds of glucose metabolism disorders than HIV-negative controls but were rarely aware of their diagnosis. Intensive glucose metabolism disorder screening and education are needed in HIV clinics in sub-Saharan Africa. Further research should determine how glucose metabolism disorders might be related to immune reconstitution.     

Is Metabolic Flexibility Altered in Multiple Sclerosis Patients?

Objectives

Metabolic flexibility is defined as ability to adjust fuel oxidation to fuel availability. Multiple sclerosis (MS) results in reduced muscle strength and exercise intolerance. We tested the hypothesis that altered metabolic flexibility contributes to exercise intolerance in MS patients.

Methods

We studied 16 patients (all on glatiramer) and 16 matched healthy controls. Energy expenditure (EE), and carbohydrate (COX) and lipid oxidation (LOX) rates were determined by calorimetry, before and after an oral glucose load. We made measurements either at rest (canopy device) or during 40 min low-grade (0.5 W/kg) exercise (metabolic chamber). We also obtained plasma, and adipose tissue and skeletal muscle dialysate samples by microdialysis to study tissue-level metabolism under resting conditions.

Results

At rest, fasting and postprandial plasma glucose, insulin, and free fatty acid levels did not differ between patients and controls. Fasting and postprandial COX was higher and LOX lower in patients. In adipose, fasting and postprandial dialysate glucose, lactate, and glycerol levels were higher in patients vs. controls. In muscle, fasting and postprandial dialysate metabolite levels did not differ significantly between the groups. During exercise, EE did not differ between the groups. However, COX increased sharply over 20 min in patients, without reaching a steady state, followed by an immediate decrease within the next 20 min and fell even below basal levels after exercise in patients, compared to controls.

Conclusions

Glucose tolerance is not impaired in MS patients. At rest, there is no indication for metabolic inflexibility or mitochondrial dysfunction in skeletal muscle. The increased adipose tissue lipolytic activity might result from glatiramer treatment. Autonomic dysfunction might cause dysregulation of postprandial thermogenesis at rest and lipid mobilization during exercise.     

Autophagy-Associated Atrophy and Metabolic Remodeling of the Mouse Diaphragm after Short-Term Intermittent Hypoxia

Background

Short-term intermittent hypoxia (IH) is common in patients with acute respiratory disorders. Although prolonged exposure to hypoxia induces atrophy and increased fatigability of skeletal muscle, the response to short-term IH is less well known. We hypothesized that the diaphragm and limb muscles would adapt differently to short-term IH given that hypoxia stimulates ventilation and triggers a superimposed exercise stimulus in the diaphragm.

Methods

We determined the structural, metabolic, and contractile properties of the mouse diaphragm after 4 days of IH (8 hours per day, 30 episodes per hour to a FiO2 nadir=6%), and compared responses in the diaphragm to a commonly studied reference limb muscle, the tibialis anterior. Outcome measures included muscle fiber size, assays of muscle proteolysis (calpain, ubiquitin-proteasome, and autophagy pathways), markers of oxidative stress and mitochondrial function, quantification of intramyocellular lipid and lipid metabolism genes, type I myosin heavy chain (MyHC) expression, and in vitro contractile properties.

Results

After 4 days of IH, the diaphragm alone demonstrated significant atrophy (30% decrease of myofiber size) together with increased LC3B-II protein (2.4-fold) and mRNA markers of the autophagy pathway (LC3B, Gabarapl1, Bnip3), whereas active calpain and E3 ubiquitin ligases (MuRF1, atrogin-1) were unaffected in both muscles. Succinate dehydrogenase activity was significantly reduced by IH in both muscles. However, only the diaphragm exhibited increased intramyocellular lipid droplets (2.5-fold) after IH, along with upregulation of genes linked to activated lipid metabolism. In addition, although the diaphragm showed evidence for acute fatigue immediately following IH, it underwent an adaptive fiber type switch toward slow type I MyHC-expressing fibers, associated with greater intrinsic endurance of the muscle during repetitive stimulation in vitro.

Conclusions

Short-term IH induces preferential atrophy in the mouse diaphragm together with increased autophagy and a rapid compensatory metabolic adaptation associated with enhanced fatigue resistance.     

Diabetes Mellitus and Prediabetes on Kidney Transplant Waiting List- Prevalence,Metabolic Phenotyping and Risk Stratification Approach

Background

Despite a significant prognostic impact, little is known about disturbances in glucose metabolism among kidney transplant candidates. We assess the prevalence of diabetes mellitus (DM) and prediabetes on kidney transplant waiting list, its underlying pathophysiology and propose an approach for individual risk stratification.

Methods

All patients on active kidney transplant waiting list of a large European university hospital transplant center were metabolically phenotyped.

Results

Of 138 patients, 76 (55%) had disturbances in glucose metabolism. 22% of patients had known DM, 3% were newly diagnosed. 30% were detected to have prediabetes. Insulin sensitivity and-secretion indices allowed for identification of underlying pathophysiology and risk factors. Age independently affected insulin secretion, resulting in a relative risk for prediabetes of 2.95 (95%CI 1.38–4.83) with a cut-off at 48 years. Body mass index independently affected insulin sensitivity as a continuous variable.

Conclusions

The prevalence of DM or prediabetes on kidney transplant waiting list is as high as 55%, with more than one third of patients previously undiagnosed. Oral glucose tolerance test is mandatory to detect all patients at risk. Metabolic phenotyping allows for differentiation of underlying pathophysiology and provides a basis for early individual risk stratification and specific intervention to improve patient and allograft outcome.     

Endurance Training Inhibits Insulin Clearance and IDE Expression in Swiss Mice

Introduction

Endurance training improves peripheral insulin sensitivity in the liver and the skeletal muscle, but the mechanism for this effect is poorly understood. Recently, it was proposed that insulin clearance plays a major role in both glucose homeostasis and insulin sensitivity. Therefore, our goal was to determine the mechanism by which endurance training improves insulin sensitivity and how it regulates insulin clearance in mice.

Methods

Mice were treadmill-trained for 4 weeks at 70–80% of maximal oxygen consumption (VO₂ max) for 60 min, 5 days a week. The glucose tolerance and the insulin resistance were determined using an IPGTT and an IPITT, respectively, and the insulin decay rate was calculated from the insulin clearance. Protein expression and phosphorylation in the liver and the skeletal muscle were ascertained by Western blot.

Results

Trained mice exhibited an increased VO₂ max, time to exhaustion, glucose tolerance and insulin sensitivity. They had smaller fat pads and lower plasma concentrations of insulin and glucose. Endurance training inhibited insulin clearance and reduced expression of IDE in the liver, while also inhibiting insulin secretion by pancreatic islets. There was increased phosphorylation of both the canonical (IR-AKT) and the non-canonical (CaMKII-AMPK-ACC) insulin pathways in the liver of trained mice, whereas only the CaMKII-AMPK pathway was increased in the skeletal muscle.

Conclusion

Endurance training improved glucose homeostasis not only by increasing peripheral insulin sensitivity but also by decreasing insulin clearance and reducing IDE expression in the liver.     

Chronic Exercise Increases Plasma Brain-Derived Neurotrophic Factor Levels,Pancreatic Islet Size,and Insulin Tolerance in a TrkB-Dependent Manner

Background

Physical exercise improves glucose metabolism and insulin sensitivity. Brain-derived neurotrophic factor (BDNF) enhances insulin activity in diabetic rodents. Because physical exercise modifies BDNF production, this study aimed to investigate the effects of chronic exercise on plasma BDNF levels and the possible effects on insulin tolerance modification in healthy rats.

Methods

Wistar rats were divided into five groups: control (sedentary, C); moderate- intensity training (MIT); MIT plus K252A TrkB blocker (MITK); high-intensity training (HIT); and HIT plus K252a (HITK). Training comprised 8 weeks of treadmill running. Plasma BDNF levels (ELISA assay), glucose tolerance, insulin tolerance, and immunohistochemistry for insulin and the pancreatic islet area were evaluated in all groups. In addition, Bdnf mRNA expression in the skeletal muscle was measured.

Principal Findings

Chronic treadmill exercise significantly increased plasma BDNF levels and insulin tolerance, and both effects were attenuated by TrkB blocking. In the MIT and HIT groups, a significant TrkB-dependent pancreatic islet enlargement was observed. MIT rats exhibited increased liver glycogen levels following insulin administration in a TrkB-independent manner.

Conclusions/Significance

Chronic physical exercise exerted remarkable effects on insulin regulation by inducing significant increases in the pancreatic islet size and insulin sensitivity in a TrkB-dependent manner. A threshold for the induction of BNDF in response to physical exercise exists in certain muscle groups. To the best of our knowledge, these are the first results to reveal a role for TrkB in the chronic exercise-mediated insulin regulation in healthy rats.     

Effects of Methane-Rich Saline on the Capability of One-Time Exhaustive Exercise in Male SD Rats

Purpose

To explore the effects of methane-rich saline (CH₄ saline) on the capability of one-time exhaustive exercise in male SD rats.

Methods

Thirty rats were equally divided into to three groups at random: control group (C), placebo group (P) and methane saline group (M). Rats in M group underwent intraperitoneal injection of CH₄ saline, and the other two groups simultaneously underwent intraperitoneal injection of normal saline. Then, the exercise capability of rats was tested through one-time exhaustive treadmill exercise except C group. Exercise time and body weight were recorded before and after one-time exhaustive exercise. After exhaustive exercise, the blood and gastrocnemius samples were collected from all rats to detect biochemical parameters in different methods.

Results

It was found that the treadmill running time was significantly longer in rats treated with CH₄ saline. At the same time, CH₄ saline reduced the elevation of LD and UN in blood caused by one-time exhaustive exercise. The low level of blood glucose induced by exhaustive exercise was also normalized by CH₄ saline. Also CH₄ saline lowered the level of CK in plasma. Furthermore, this research indicated that CH₄ saline markedly increased the volume of T-AOC in plasma and alleviated the peak of TNF-α in both plasma and gastrocnemius. From H&E staining, CH₄ saline effectively improved exercise-induced structural damage in gastrocnemius.

Conclusions

CH₄ saline could enhance exercise capacity in male SD rats through increase of glucose aerobic oxidation, improvement of metabolic clearance and decrease of exhaustive exercise-induced gastrocnemius injury.