Diabetic Muscle Research Articles

Tocotrienol-rich fraction supplementation reduces hyperglycemia-induced skeletal muscle damage through regulation of insulin signaling and oxidative stress in type 2 diabetic mice

Chronic hyperglycemia induces impairment of muscle growth and development of diabetes mellitus (DM). Since skeletal muscle is the major site for disposal of ingested glucose, impaired glucose metabolism causes imbalance between protein synthesis and degradation which adversely affects physical mobility.In this study, we investigated the effect of tocotrienol-rich fraction (TRF) supplementation on skeletal muscle damage in diabetic mice. Diabetes was induced by a high-fat diet with streptozotocin (STZ) injection (100 mg/kg) in male C57BL/6J mice. After diabetes was induced (fasting blood glucose levels≥250 mg/dl), normal control (CON) and diabetic control (DMC) groups were administrated with olive oil, while TRF treatment groups were administrated with TRF (dissolved in olive oil) at low dose (100 mg/kg BW, LT) or high dose (300 mg/kg BW, HT) by oral gavage for 12 weeks.TRF supplementation ameliorated muscle atrophy, plasma insulin concentration and homeostatic model assessment estimated insulin resistance in diabetic mice. Moreover, TRF treatment up-regulated IRS-1 and Akt levels accompanied by increased translocation of GLUT4. Furthermore, TRF increased mitochondrial biogenesis by activating SIRT1, SIRT3 and AMPK in diabetic skeletal muscle. These changes were in part mechanistically explained by reduced levels of skeletal muscle proteins related to oxidative stress (4-hydroxynonenal, protein carbonyls, Nrf2 and HO-1), inflammation (NFkB, MCP-1, IL-6 and TNF-α), and apoptosis (Bax, Bcl₂ and caspase-3) in diabetic mice. Taken together, these results suggest that TRF might be useful as a beneficial nutraceutical to prevent skeletal muscle atrophy associated with diabetes by regulating insulin signaling via AMPK/SIRT1/PGC1α pathways in type 2 diabetic mice.

Store operated calcium channels are associated with diabetic cystopathy in streptozotocin‑induced diabetic rats.

Store operated calcium channels (SOCCs) have been suggested to play a critical role in many diabetic complications. Diabetic cystopathy (DCP) is common in patients with diabetes, but the role of SOCCs in DCP is still unclear. The aim of the present study was to investigate the role of SOCCs in DCP with streptozocin (STZ)-induced diabetic rats. Specifically, the authors investigated whether SOCCs were altered in streptozocin (STZ)-induced diabetic rats and, if so, how this may contribute to the contraction of bladder detrusor strips and the intracellular Ca2+ concentration of bladder smooth muscle cells in diabetic rats. Cyclopiazonic acid (CPA, 10 µM) and SKF-96365 (10 µM) were used to activate and inhibit SOCCs respectively, to research the effects of SOCCs on the contraction of the bladder detrusor strips in normal and STZ-induced diabetic rats at the 4th, 8th and 12th week after the diabetic rat model was established. The changes of intracellular Ca2+ were also evaluated under confocal microscopy with pretreated Fluo-4AM. In addition, the expressions of Orai1 and STIM1 were detected by reverse transcription-quantitative polymerase chain reaction and western blotting at different time points. According to the results, the contractive frequency of diabetic bladder muscle strips was higher than that of controls in the 4th and 8th week. The increased fluorescence intensity was detected after using CPA and SKF-96365 in diabetic groups. The expressions of Orai1 and STIM1 changed in a time-dependent manner.

Diabetic muscle infarction in end-stage renal disease: A scoping review on epidemiology, diagnosis and treatment.

Diabetic muscle infarction (DMI) refers to spontaneous ischemic necrosis of skeletal muscle among people with diabetes mellitus, unrelated to arterial occlusion. People with DMI may have coexisting end-stage renal disease (ESRD) but little is known about its epidemiology and clinical outcomes in this setting. This scoping review seeks to investigate the characteristics, clinical features, diagnostic evaluation, management and outcomes of DMI among people with ESRD. Electronic database (PubMed/MEDLINE, CINAHL, SCOPUS and EMBASE) searches were conducted for (“diabetic muscle infarction” or “diabetic myonecrosis”) and (“chronic kidney disease” or “renal impairment” or “dialysis” or “renal replacement therapy” or “kidney transplant”) from January 1980 to June 2017. Relevant cases from reviewed bibliographies in reports retrieved were also included. Data were extracted in a standardized form. A total of 24 publications with 41 patients who have ESRD were included. The mean age at the time of presentation with DMI was 44.2 years. Type 2 diabetes was present in 53.7% of patients while type 1 in 41.5%. In this cohort, 60.1% were receiving hemodialysis, 21% on peritoneal dialysis and 12.2% had kidney transplantation. The proximal lower limb musculature was the most commonly affected site. Muscle pain and swelling were the most frequent manifestation on presentation. Magnetic resonance imaging (MRI) provided the most specific findings for DMI. Laboratory investigation findings are usually non-specific. Non-surgical therapy is usually used in the management of DMI. Short-term prognosis of DMI is good but recurrence occurred in 43.9%. DMI is an uncommon complication in patients with diabetes mellitus, including those affected by ESRD. In comparison with unselected patients with DMI, the characteristics and outcomes of those with ESRD are generally similar. DMI may also occur in kidney transplant recipients, including pancreas-kidney transplantation. MRI is the most useful diagnostic investigation. Non-surgical treatment involving analgesia, optimization of glycemic control and initial bed rest can help to improve recovery rate. However, recurrence of DMI is relatively frequent.

3:45 PM Abstract No. 287 Increase in muscle mass after transjugular intrahepatic portosystemic shunt (TIPS) creation is a prognostic indicator for survival in cirrhosis

To assess changes in skeletal muscle volume and density after TIPS creation. Patients with cirrhosis undergoing TIPS creation at a single institution between 2004 and 2015, and who had available pre- and post-TIPS contrast-enhanced CT scans, were reviewed (n = 80). Subjects who had received liver transplantation prior to TIPS creation or during the observation period (n = 4) were excluded. Cross sectional muscle area and density (psoas, paraspinal, abdominal wall) were measured with free-hand region of interest at the mid L4 vertebral body level before and after TIPS creation. Differences were compared using the paired t-test. Pairwise correlation analysis was performed to evaluate associations between baseline muscle area and clinical characteristics with post-TIPS changes. Predictors of overall survival were assessed using univariate and multivariate Cox proportional hazard models adjusted for age, sex, HCV infection, hepatocellular carcinoma, diabetes, MELD score and baseline muscle measurements. P values < 0.05 were considered significant. Significant increases in psoas, paraspinal, and total muscle areas were observed after TIPS creation (P <0.001, 0.004, 0.002). A significant increase in post-TIPS psoas muscle attenuation was also observed (3.1 ± 8.5 HU, P = 0.022). In multivariate analysis, increases in psoas (HR = 0.14, P = 0.016), paraspinal (HR = 0.15, P = 0.016), abdominal (HR = 0.05, P = 0.005), core (HR = 0.06, P = 0.001) and total (HR = 0.05, P = 0.003) muscle areas after TIPS creation predicted significantly increased survival rates compared to those with no change. Changes in core muscle area following TIPS creation were not predicted by patient demographics, comorbidities, or pre- and post-TIPS liver function studies. Cross-sectional area of truncal muscles significantly increased after TIPS creation and correlated with improved survival. These parameters can complement other determinants in the assessment of prognosis after TIPS creation. Future research will elucidate the prognostic impact of sarcopenia for TIPS creation, and will increase understanding of potential metabolic changes induced after portosystemic shunting.

Exercise training impacts exercise tolerance and bioenergetics in gastrocnemius muscle of non-obese type-2 diabetic Goto-Kakizaki rat in vivo

The functional and bioenergetics impact of regular physical activity upon type-2 diabetic skeletal muscle independently of confounding factors of overweight remains undocumented. Here, gastrocnemius muscle energy fluxes, mitochondrial capacity and mechanical performance were assessed noninvasively and longitudinally in non-obese diabetic Goto-Kakizaki rats using magnetic resonance (MR) imaging and dynamic 31-phosphorus MR spectroscopy (31P-MRS) throughout a 6-min fatiguing bout of exercise performed before, in the middle (4-week) and at the end of an 8-week training protocol consisting in 60-min daily run on a treadmill. The training protocol reduced plasmatic insulin level (−61%) whereas blood glucose and non-esterified fatty acids levels remained unaffected, thereby indicating an improvement of insulin sensitivity. It also increased muscle mitochondrial citrate synthase activity (+45%) but this increase did not enhance oxidative ATP synthesis capacity in working muscle in vivo while glycolytic ATP production was increased (+33%). On the other hand, the training protocol impaired maximal force-generating capacity (−9%), total amount of force produced (−12%) and increased ATP cost of contraction (+32%) during the fatiguing exercise. Importantly, these deleterious effects were transiently worsened in the middle of the 8-week period, in association with reduced oxidative capacity and increased basal [Pi]/[PCr] ratio (an in vivo biomarker of muscle damage). These data demonstrate that the beneficial effect of regular training on insulin sensitivity in non-obese diabetic rat occurs separately from any improvement in muscle mitochondrial function and might be linked to an increased capacity for metabolizing glucose through anaerobic process in exercising muscle.

Co-Administered Vitamin E Isoforms d-α-tocopherol and d-δ-tocotrienol Rich Fraction Promote Regeneration of Skeletal Muscle in Diabetics

In diabetes the structural and functional recovery of skeletal muscle is impaired due to persistent hyperglycemia-induced oxidative stress. Vitamin E is known to be essential antioxidant for maintains the skeletal muscle homeostasis thus preventing oxidative damages. This study is designed to explore the effect of d-α-tocopherol and d-δ-tocotrienol rich fraction (d-δ-TRF) on crushed muscle regeneration in both healthy and diabetic rats. Diabetes was induced through single subcutaneous injection of aqueous alloxan at the dose of 100 mg/kg. Twenty four albino rats were divided into four groups; healthy control, diabetic control, healthy treated and diabetic treated. Treated groups received 100 mg/kg of d-α-tocopherol and d-δ-TRF each, orally, daily for three weeks. Through a horizontal mid-thigh skin incision and splitting of the fascia gluteus maximus was approached and crushed with Kocher’s forceps. Skin wound was closed with an absorbable suture. The crush-induced degenerative and regenerative changes in the muscle were studied by assessing the histological features, histomorphological measurements and biochemical analyses at the end of 3^rd weeks. One- way ‘ANOVA’ and Student’s t-test were used for statistical analysis. All results revealed that the vitamin E isoforms have potency to maintain glycemic level, improve the antioxidant capacity and hasten the process of regeneration, revascularization, reinnervation and connective tissue remodeling in skeletal muscle after crush injury. It is therefore, concluded that the vitamin E isoforms are useful nutritional supplements for skeletal muscle functional and structural recovery in both healthy and diabetics.

Clinico-radiological characteristics and not laboratory markers are useful in diagnosing diabetic myonecrosis in Asian Indian patients with type 2 diabetes mellitus: A 10-year experience from South India.

Introduction:Diabetic myonecrosis or muscle infarction is an unusual complication of Type 2 Diabetes, usually associated with longstanding disease. It commonly presents as an acute non-traumatic palpable swelling of the affected muscle with predilection for the quadriceps and thigh muscles, often accompanied by retinopathy and nephropathy.Methodology:A retrospective review of the medical records of patients admitted with diabetic myonecrosis under the Department of Endocrinology, Christian Medical College Vellore over a period of ten years(2006-2015) was done. Data pertaining to clinical, biochemical and radiological characteristics were obtained and treatment modalities and outcomes were recorded.Results and Analysis:A total of n = 4 patients with diabetic myonecrosis and completed clinical data were included in the study. In our present series, the mean age at presentation was 45.5 years (±7.3 years), the mean duration of the diabetes was 9.0 years (±2.5 years)with an equal distribution of male and female subjects. The mean HbA1c (9.5 ± 0.6%) was suggestive of poor glycemic control at presentation with all (100%) the patients in our series having concomitant one or more microvascular complications. While laboratory parameters of elevated CPK or LDH were mostly normal, the findings of T1 hyperintense and T2 hypointense heterogenous lower limb lesions were present in all the subjects (n = 4). Conservative management with bed rest, analgesics and good glycemic control were effective in good clinical improvement over a period of 1-2 months.Conclusions:Our series of diabetic myonecrosis in Indian patients with Type 2 diabetes mellitus, elucidates the varied clinical presentations, with MRI findings rather than laboratory markers being the mainstay of diagnosis.

FoxO Transcription Factors Are Critical Regulators of Diabetes-Related Muscle Atrophy

Insulin deficiency and uncontrolled diabetes lead to a catabolic state with decreased muscle strength, contributing to disease-related morbidity. FoxO transcription factors are key mediators of insulin action. To study their role in diabetic muscle wasting, we created mice with musclespecific triple knockout of FoxO1/3/4 and induced diabetes in these M-FoxO-TKO mice with streptozotocin (STZ). Muscle mass and myofiber area were decreased 20-30% in STZ-Diabetes mice due to increased ubiquitinproteasome degradation and autophagy, characterized by increased pULK1 and LC3-II. Both the muscle loss and markers of increased degradation/autophagy were completely prevented in STZ-FoxO-TKO mice. Transcriptomic analyses revealed FoxO-dependent increases in ubiquitin-mediated proteolysis pathways in STZ-Diabetes, including regulation of Fbxo32 (Atrogin1), Trim63 (MuRF1), Bnip3L, and Gabarapl. These same genes were increased 1.4- to 3.3-fold in muscle from type 1 diabetics after shortterm insulin deprivation. Thus, FoxO-regulated genes play a rate-limiting role in increased protein degradation and muscle atrophy in insulin-deficient diabetes.

Diabetic muscle infarction

Diabetic muscle infarction is an underdiagnosed and underreported complication of long-standing diabetes mellitus occurring in a middle-aged person with symptoms simulating infective or inflammatory condition most commonly involving the thigh muscles, legs, and arms, in decreasing order of frequency. Magnetic resonance imaging is the diagnostic modality of choice showing diffuse hyperintense signal involving the muscles and deep fascia on T2 images. It is a self-limiting condition which resolves simply by rest and analgesic; therefore, being aware of this condition is necessary to avoid unnecessary interventions.

Implication of altered ubiquitin-proteasome system and ER stress in the muscle atrophy of diabetic rats

BackgroundSkeletal muscle is adversely affected in type-1 diabetes, and excessively stimulated ubiquitin-proteasome system (UPS) was found to be a leading cause of muscle wasting or atrophy. The role of endoplasmic reticulum (ER) stress in muscle atrophy of type-1 diabetes is not known. Hence, we investigated the role of UPS and ER stress in the muscle atrophy of chronic diabetes rat model. MethodsDiabetes was induced with streptozotocin (STZ) in male Sprague-Dawley rats and were sacrificed 2- and 4-months thereafter to collect gastrocnemius muscle. In another experiment, 2-months post-STZ-injection diabetic rats were treated with MG132, a proteasome inhibitor, for the next 2-months and gastrocnemius muscle was collected. ResultsThe muscle fiber cross-sectional area was diminished in diabetic rats. The expression of UPS components: E1, MURF1, TRIM72, UCHL1, UCHL5, ubiquitinated proteins, and proteasome activity were elevated in the diabetic rats indicating activated UPS. Altered expression of ER-associated degradation (ERAD) components and increased ER stress markers were detected in 4-months diabetic rats. Proteasome inhibition by MG132 alleviated alterations in the UPS and ER stress in diabetic rat muscle. ConclusionIncreased UPS activity and ER stress were implicated in the muscle atrophy of diabetic rats and proteasome inhibition exhibited beneficiary outcome.

Coriolus versicolor aqueous extract ameliorates insulin resistance with PI3K/Akt and p38 MAPK signaling pathways involved in diabetic skeletal muscle.

Patients with type 2 diabetes mellitus (T2DM) are usually with poor immunity and easier to suffer from cancer and microbial infections. Herein, we report an efficient anti-diabetic medicinal mushroom, Coriolus versicolor (CV). This study aimed to investigate the anti-diabetic and anti-insulin-resistance effects of CV aqueous extract in myoblasts (L6 cells) and skeletal muscle of T2DM rat. Our results showed that CV extract treatment significantly reduced blood glucose levels of T2DM rats, whereas CV extract increased glucose consumption in insulin resistant L6 cells. Besides, the translocation and expression of glucose transporter 4 were enhanced by CV extract, which indicated that CV extract was effective in diabetic skeletal muscle. Moreover, CV extract treatments resulted in remarkable anti-insulin-resistance effects, which was reflected by the change of gene and protein expression levels in PI3K/Akt and p38 MAPK pathways. PI3K inhibitor, LY29004, and p38 MAPK inhibitor, SB203580 confirmed it further. In conclusion, our results demonstrated that the CV extract exhibited anti-diabetic and anti-insulin-resistance effects in diabetic skeletal muscle, and the effects were mediated by PI3K/Akt and p38 MAPK pathways. These findings are remarkable when considering the use of commercially available CV by diabetic patients who also suffer from cancer or microbial infections.

GLUT-1 IS A PROMISING TARGET FOR ATP DEPLETION ON DIABETIC ENERGY DEFICIENCY SYNDROME

Diabetes is a metabolic syndrome which characterized with insulin insensitivity, lack of GLUT-4 membrane presentation and ATP deficiency. ATP is needed for substrate phosphorylation, signalling pathways, protein translation and cellular survival. Since GLUT-1 was discovered as alternative glucose transporter on muscle membrane, some studies started to investigate it more. This study aimed to investigate GLUT-1 presentation on diabetes muscle membrane of rat model in time. Diabetes was obtained from a 50 mg/kg B.W of streptozotocin intra peritoneal injection on rat. We found that GLUT-1 presentation increased significantly in time of diabetic stages. It correlated negatively with GLUT-4 presentation and mortality. Eccentric downhill running on diabetic rat model improved GLUT-1 presentation and blood glucose level. It was promising for diabetes management therapy at the future.

Recurrent diabetic muscle infarction, a rare complication of diabetes: a case report

Diabetic muscle infarction is a rare complication of diabetes mellitus that presents as a localized, exquisitely painful swelling and limited range of motion of the involved extremity. The onset is usually acute, persists for several weeks and resolves spontaneously over several weeks to months without the need for intervention. However, as diabetes mellitus is an immunocompromised state and any painful swelling in the limbs is often taken as infectious in aetiology, the patient is inadvertently investigated with invasive procedures and is started on unnecessary antibiotics, adding to the burden of management. Keeping in view the low threshold for starting antibiotics in painful limb swelling in diabetes mellitus in our setting, we hereby describe a case of recurrent painful diabetic muscle infarction, first involving the right upper and later the right lower limb, managed with physical rest and analgesics. This case emphasizes that the treating physician keep this rare complication of diabetes mellitus in consideration in the respective clinical scenario and adopt a less aggressive (a noninvasive method like ultrasound) rather than a more aggressive (an invasive method like muscle biopsy) approach in diagnosis and take a similar approach towards management.

Resistance training increases fibroblast growth factor-21 and irisin levels in the skeletal muscle of Zucker diabetic fatty rats.

[Purpose]Although the fibroblast growth factor-21 (FGF-21) and irisin roles are well demonstrated in metabolic disease, there have been no reports investigating the effect of resistance exercise on FGF-21 and irisin levels in diabetic skeletal muscles. Therefore, this study aimed to investigate the change of FGF-21 and irisin levels in various skeletal muscles, and their association with muscle strength, following 8 weeks of resistance training using Zucker diabetic fatty rats (type 2 diabetic animal models).[Methods]Twenty-four male lean (Zucker lean control, ZLC) and diabetic (Zucker diabetic fatty, ZDF) rats (age, 8 weeks old) were separated into 3 groups, lean control (ZLC-Con, n=8), diabetic control (ZDF-Con, n=8), and diabetic exercise-trained groups (ZDF-Ex, n=8). The rats in ZDF-Ex were trained to climb a 1-m vertical (85 degrees inclined) ladder with weights. Resistance training was performed with 10 repetitions/day for 12 weeks (3 days/week). The skeletal muscle levels of FGF-21 and irisin were measured using enzyme-linked immunosorbent assays.[Results]The levels of FGF-21 in the soleus (SOL) and extensor digitorum longus muscles of ZDF-Ex were higher (p<0.05) compared to levels in ZDF-Con. Additionally, we found a significantly higher irisin level in the SOL muscles of ZDF-Ex compared to that in ZDF-Con. Moreover, we found that the levels of FGF-21 (R=0.532, p=0.02) and irisin (R=0.498, p=0.03) had significant correlations with grip strength.[Conclusion]Based on these results, resistance training may be an efficient intervention for increasing FGF-21 and irisin levels in type 2 diabetic (T2DM) skeletal muscles.

Low-intensity aerobic exercise training: inhibition of skeletal muscle atrophy in high-fat-diet-induced ovariectomized rats.

[Purpose]Postmenopausal women are highly susceptible to diseases, such as obesity, type 2 diabetes, osteoporosis, or skeletal muscle atrophy and many people recognize the need for regular physical activity. Aerobic exercise training is known to improve the oxidative capacity and insulin sensitivity of skeletal muscles. This study aimed to investigate the role of low-intensity aerobic exercise training on skeletal muscle protein degradation or synthesis in the plantaris muscles of high-fat-fed ovariectomized rats.[Methods]Ovariectomized female rats were divided into two groups: a high-fat diet-sedentary group (HFD), and a high-fat diet-aerobic exercise group (HFD+EX). The exercise group exercised aerobically on a treadmill 5 days/week for 8 weeks. The rats progressively ran 30 min/day at 15 m/min, up to 40 min/day at 18 m/min, 0% slope, in the last 4 weeks.[Results]Although aerobic exercise led to significantly increased AMP-activated protein kinase (AMPK) phosphorylation at Thr172, phosphorylation of the mammalian target of rapamycin (mTOR) substrate Thr389 S6K1 level did not decrease. Additionally, even though Akt activity did not increase at Ser473, the atrogin-1 level significantly decreased in the exercise group compared to the non-exercise group. Immunohistochemical staining revealed that high-fat-induced TSC2 protein expression was eliminated in response to aerobic exercise.[Conclusion]These results suggest that aerobic exercise can inhibit skeletal muscle protein degradation, but it cannot increase protein synthesis in the plantaris muscle of high-fat-fed ovariectomized rats. Our findings have implications in understanding skeletal muscle mass maintenance with low intensity aerobic exercise in post-menopausal women.

Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease.

We explored whether growth differentiation factor 15 (GDF15) affects the histological severity of non-alcoholic fatty liver disease (NAFLD) independent of insulin resistance. In a biopsy-proven NAFLD cohort, we measured serum GDF15 levels using enzyme-linked immunosorbent assays. Among 190 subjects (mean age, 53±14years; men, 52.1%), 72 (men, 65.3%) and 78 (men, 44.9%) were diagnosed with biopsy-proven non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) respectively. GDF15 levels were significantly higher in NASH patients than in controls (P=.010) or NAFL patients (P=.001). Subjects with advanced fibrosis (≥F3) also showed higher GDF15 levels compared to the others (F0-2; P<.001). Among NAFLD patients, the highest quartile of GDF15 levels was significantly associated with a risk of advanced fibrosis even after adjustment for age, gender, body mass index, smoking status, hypertension, diabetes, aspartate aminotransferase, platelet, albumin, insulin resistance and low skeletal muscle mass (odds ratio, 4.27; 95% confidence interval, 1.04-17.63), but not with NASH risk. GDF15 levels showed a significant positive correlation with liver stiffness (Spearman's ρ, .525; P<.001). Palmitate treatment increased the GDF15 mRNA expression level significantly in Kupffer cells, but not in hepatocytes. In LX-2 cells, GDF15 treatment resulted in enhanced expression of α-smooth muscle actin and collagen I, as well as phosphorylation of SMAD2 and SMAD3. Our findings suggest that GDF15 may serve as a novel biomarker of advanced fibrosis in NAFLD, thereby indicating the need for urgent anti-fibrotic pharmacotherapy.

Predictive simulation of diabetic gait: Individual contribution of ankle stiffness and muscle weakening

Diabetic neuropathic individuals present massive muscle strength reduction at the ankle plantar- and dorsiflexors and increased joint stiffness. Our aim is to investigate the adaptation strategies to these musculoskeletal alterations during walking by means of predictive simulations. We used a seven segment planar musculoskeletal model actuated by eight Hill-type muscles in each leg. The effect of all passive tissue in muscles and other joint structures was modeled by net passive joint moment curves. The predictive simulations were generated by solving an optimal control problem that minimized a cost function, including effort and tracking terms, using direct collocation and a commercial optimal control package. We simulate four conditions to represent the weakening of the distal muscles triceps sural (TS) and tibialis anterior (TA), and five conditions to represent the effect of increasing nonlinear ankle stiffness in flexion. The weakening of the distal muscles leads to a delayed action of the TS and a progressive decrease of the gastrocnemius peak force in the push-off phase. This distal deficit is compensated by a larger hip flexion moment resulting from an increase in the iliopsoas muscle force in this phase, known as the hip strategy. The adaptation mechanisms observed in response to an increase in ankle stiffness include the hip strategy and the exploitation of the passive joint structures as springs, which store energy during midstance and release it during push-off, reducing TS force and power in this phase and leading to a consistent decrease in the overall muscle force levels.

Transendothelial movement of adiponectin is restricted by glucocorticoids.

Altered permeability of the endothelial barrier in a variety of tissues has implications both in disease pathogenesis and treatment. Glucocorticoids are potent mediators of endothelial permeability, and this forms the basis for their heavily prescribed use as medications to treat ocular disease. However, the effect of glucocorticoids on endothelial barriers elsewhere in the body is less well studied. Here, we investigated glucocorticoid-mediated changes in endothelial flux of Adiponectin (Ad), a hormone with a critical role in diabetes. First, we used monolayers of endothelial cells in vitro and found that the glucocorticoid dexamethasone increased transendothelial electrical resistance and reduced permeability of polyethylene glycol (PEG, molecular weight 4000 Da). Dexamethasone reduced flux of Ad from the apical to basolateral side, measured both by ELISA and Western blotting. We then examined a diabetic rat model induced by treatment with exogenous corticosterone, which was characterized by glucose intolerance and hyperinsulinemia. There was no change in circulating Ad but less Ad protein in skeletal muscle homogenates, despite slightly higher mRNA levels, in diabetic vs control muscles. Dexamethasone-induced changes in Ad flux across endothelial monolayers were associated with alterations in the abundance of select claudin tight junction (TJ) proteins. shRNA-mediated knockdown of one such gene, claudin-7, in HUVEC resulted in decreased TEER and increased adiponectin flux, confirming the functional significance of Dex-induced changes in its expression. In conclusion, our study identifies glucocorticoid-mediated reductions in flux of Ad across endothelial monolayers in vivo and in vitro This suggests that impaired Ad action in target tissues, as a consequence of reduced transendothelial flux, may contribute to the glucocorticoid-induced diabetic phenotype.

The effects of alpha-lipoic acid on diabetic myopathy.

Increased oxidative stress and impaired antioxidant defense are important mechanisms in the pathogenesis of diabetic myopathy. Since diabetes mellitus type 1 decreases muscle regeneration capacity the present study was designed to determine the influence of alpha-lipoic acid (ALA), a potent biological antioxidant, on the process of regeneration of diabetic rat skeletal muscles. 40 Wistar rats were divided into three groups: control (n=8), untreated diabetic group (n=16) and ALA treated diabetic group (n=16). The regeneration process was provoked in streptozotocin-induced diabetic rats in both slow (m.soleus, SOL) and fast (m.extensor digitorum longus, EDL) skeletal muscles by intramuscular injection of myotoxin bupivacaine. At intervals of 10 days and 4 weeks, muscle histochemical and morphometrical analysis (fiber cross areas and fiber type distribution) was performed. Changes induced by diabetes are evident in redistribution of muscle fibers and in significant level of atrophy. After 4 weeks of diabetes, glycolytic muscle fibers are dominant in both slow and fast muscles. Muscle atrophy is present in all fiber types except in type I of slow skeletal muscle. Treatment with ALA reduce changes in the morphological properties caused by diabetes mellitus type 1 in slow and fast rat skeletal muscles during the process of regeneration. Treatment with lipoic acid during 4 weeks has shown effects on the redistribution of muscle fibers, and can prevent atrophy in slow and fast diabetic muscle.

Flavanol-Rich Lychee Fruit Extract Prevents Diabetes-induced Muscle Loss And Palmitate-induced Myotube Loss

Diabetes-induced muscle loss is associated with stimulated the muscle RING-finger protein 1 (MuRF1), a muscle specific E3 ubiquitin ligase. Elevated lipid metabolites impair myogenesis. Flavanol-rich lychee fruit extract (FRLFE) exhibited anti-diabetic and -obesity properties which would be an alternative approach for maintaining muscle homeostasis. PURPOSE: The underlying mechanisms of FRLFE on maintaining muscle homeostasis was studied in vivo and in vitro. METHODS: Dietary (10 wk) FRLFE supplementation (200 mg/kg diet) on the skeletal muscle size and transcription factors such as NF-κB and Foxo3a involved in regulation of MuRF1 were investigated in diabetic db/db mice (n=10/per group). The roles of FRLFE on cell cycle and senescent phenotype were investigated in palmitate-induced insulin resistance in C2C12 muscle cells. The statistical significance of the differences among the groups (P < 0.05) was determined by one-way ANOVA and following post hoc assessment by Student-Newman-Keuls Method. RESULTS: The average cross-sectional area was significantly increased by 1.6-fold after administration of FRLFE compared with non-treated db/db mice (420μm2). Prevention of muscle loss by FRLFE was associated with down regulation of MuRF1 mRNA expression (410% vs. 100%, p<0.05). Decreased NF-κB expression in the nuclear fraction was observed in FRLFE treated db/db mice compared with untreated mice (260% vs. 60%, p<0.05). At transcriptional level, FRLFE abated ceramide-induced MuRF1 promoter activity (200% vs. 100%, p<0.05). Restoration of SIRT1 expression (30% vs. 150%, p<0.05) prevented Foxo3a nuclear localization in FRLFE treated db/db mice. A strong β-galactosidase staining positive signal was observed in the palmitate-treated myoblasts. For cell cycle analysis, significantly increased proportion of cells in G2-phase by palmitate was observed compared with group without palmitate treatment (28.9% vs. 18.3%). Weak β-galactosidase staining positive signals in accordance with decreased proportion of cells in G2-phase (21.7%) were observed in FRLFE-treated myoblasts. CONCLUSION: The efficacy of FRLFE on preserving skeletal muscle mass and myogenic process indicates that FRLFE acts as an effective supplement for diabetes and/or obesity-induced muscle atrophy.