The speed-gene study: methods, study design and preliminary results.

The Speed-Gene study aims to identify genetic variants influencing athletic performance and human locomotion using motion capture technology. Currently, 60 female participants have completed the testing protocol, and the overall aim is to recruit 283 moderately trained, healthy Southeast Asian individuals (18-45 y, BMI < 30). Participants will undergo biomechanical analysis and genetic testing. Several analyses will be performed, including (but not limited to) linear and angular kinematic analysis using motion capture technology, force plate dynamometry and genetic analyses to define novel power/torque related outcomes that would be more sensitive to allele-specific differences in athletic performance. Pretesting beverages will be provided, and activity history and current activity levels will be assessed by a questionnaire. The kinematic data will be obtained using a Qualisys Track Manager (QTM) system, and DNA will be extracted from white blood cells. The participants serve as their own controls. Although the Speed-Gene study is tightly controlled, our preliminary findings still indicate considerable individual variability. More participants and further genetic analysis are required to allow the investigation of potential underlying genetic mechanisms responsible for this individual variability.

Muscle Activation and Ground Reaction Force between Single-Leg Drop Landing and Jump Landing among Young Females during Weight-Acceptance Phase.

Single-leg drop landing (SLDL) and jump landing (SLJL) are frequently used as assessment tools for identifying potential high-risk movement patterns; thus, understanding differences in neuromuscular responses between these types of landings is essential. This study aimed to compare lower extremity neuromuscular responses between the SLDL and SLJL. Thirteen female participants performed an SLDL and SLJL from a 30-cm box height. Vertical ground reaction force (vGRF), time to peak vGRF, and surface electromyography (sEMG) data were collected. Continuous neuromuscular responses, peak vGRF, and time to peak vGRF were compared between the tasks. Statistical parametric mapping (SPM) analysis demonstrated that the SLJL had a significantly higher sEMG activity in the rectus femoris (RF), vastus lateralis (VL) and vastus medialis (VM) within the first 10% of the landing phase compared with SLDL. At 20-30% of the landing phase, sEMGs in the RF and VL during the SLDL were significantly higher compared with SLJL (p < 0.05). A higher peak vGRF and shorter time to peak vGRF was observed during SLJL (p < 0.05). In conclusion, our findings highlight that SLJL exhibited greater RF, VL, and VM activities than SLDL at initial impact (10% landing), coinciding with a higher peak vGRF and shorter time to attain peak vGRF. Our findings support the role of the quadriceps as the primary energy dissipator during the SLJL.

Dietary Supplementation with 20-Hydroxyecdysone Ameliorates Hepatic Steatosis and Reduces White Adipose Tissue Mass in Ovariectomized Rats Fed a High-Fat, High-Fructose Diet.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is defined as hepatic steatosis in combination with overweight, diabetes, or other metabolic risk factors. MAFLD affects a significant number of the global population and imposes substantial clinical and economic burdens. With no approved pharmacotherapy, current treatment options are limited to diet and exercise. Therefore, the development of medicines for MAFLD treatment or prevention is necessary. 20-Hydroxyecdysone (20E) is a natural steroid found in edible plants and has been shown to improve metabolism and dyslipidemia. Therefore, it may be useful for MAFLD treatment. Here, we aimed to determine how dietary supplementation with 20E affects fat accumulation and lipogenesis in the liver and adipose tissue of ovariectomized rats fed a high-fat, high-fructose diet (OHFFD). We found that 20E reduced hepatic triglyceride content and visceral fat deposition. 20E increased the phosphorylation of AMP-activated protein kinase and acetyl CoA carboxylase while reducing the expression of fatty acid synthase in the liver and adipose tissue. Additionally, 20E increased hepatic expression of carnitine palmitoyltransferase-1 and reduced adipose expression of sterol regulatory element-binding protein-1. In conclusion, 20E demonstrated beneficial effects in rats with OHFFD-induced MAFLD. These findings suggest that 20E may represent a promising option for MAFLD prevention or treatment.

Morphological alteration of the pancreatic islet in ovariectomized rats fed a high-fat high-fructose diet.

Diabetes and its complications are major causes of mortality worldwide. Type 2 diabetes coexists with insulin resistance and ß-cell dysfunction, which are aggravated by overconsumption and estrogen-deprived conditions. However, the morphology of pancreatic islets in a combined condition of excessive caloric intake and estrogen deficiency has never been described. Herein, we examined morphological changes in the pancreatic islets of ovariectomized (OVX) rats fed a high-fat high-fructose diet (HFFD) for 12 weeks. The histological changes in the size and number of pancreatic islets were assessed by hematoxylin-eosin and immunohistochemical staining. Enlarged pancreatic islets with fat deposition in OVX rats were accompanied by whole-body insulin resistance and hyperglycemia. The addition of a HFFD to OVX rats (OVX + HFFD) further aggravated insulin resistance, with a substantial increase in the density of enlarged pancreatic islets and fat accumulation. The augmented number of enlarged islets was correlated with elevated plasma glucose and insulin levels. Intriguingly, unlike the HFFD and OVX alone, the OVX + HFFD markedly expanded the area of insulin-producing ß-cells and glucagon-producing α-cells. Importantly, enlarged islets, pancreatic fat deposits, and diabetic states developing in OVX + HFFD conditions were resolved by estrogen replacement. Collectively, the morphological characteristics of pancreatic islets were influenced in an insulin-resistant state caused by estrogen deficiency and HFFD consumption and were distinct from each factor alone. A combination of estrogen deficiency with HFFD consumption worsened the integrity of pancreatic islets, ultimately resulting in disease progression. These findings expand our understanding of the causal relationship between pancreatic morphology and diabetes development and suggest therapeutic strategies.

Classification of Limb and Mobility Impairments in Persons With Stroke Using the STREAM.

BACKGROUND AND PURPOSE: Classification of functional impairment in persons with stroke can influence treatment planning but this information is missing in the Stroke Rehabilitation Assessment of Movement (STREAM) Scale. This study aimed to establish the classification of limb mobility impairments and item difficulty of the STREAM. METHODS: Rasch analysis was conducted on the STREAM scores to examine the person and item reliability, the item difficulty, and level of impairments. A total of 240 participants were evaluated using the STREAM, the Fugl-Meyer Stroke Assessment (FM), and the Functional Ambulation Categories (FAC). The concurrent validity of the STREAM extremity (STREAM-E) category with the FM-motor category and the STREAM mobility (STREAM-M) category with the FAC category was analyzed using the Spearman rank-order correlation. RESULTS: Person reliabilities of the STREAM-E and STREAM-M were 0.92 and 0.80, respectively. High-item reliability was observed in both STREAM-E (0.97) and STREAM-M (0.99). The STREAM items "flexes hip and knee in supine" and "rolls onto side" were the easiest items, whereas the "dorsiflexes affected ankle with knee extended" item was the most difficult item. The STREAM-E category demonstrated excellent concurrent validity with the FM-motor category (ρ = 0.83) in classifying individuals with stroke into 5 groups: mild, moderate, moderately severe, severe, and very severe limb impairment. The STREAM-M category showed a moderate correlation with the FAC category (ρ = 0.71) in categorizing persons with stroke into 3 groups: mild, moderate, and severe mobility impairment. DISCUSSION AND CONCLUSIONS: Findings can be used in the assessment and treatment planning of persons with stroke.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A373).

Hydration Status, Fluid Intake, Sweat Rate, and Sweat Sodium Concentration in Recreational Tropical Native Runners.

AIM: The purpose of this study was to evaluate hydration status, fluid intake, sweat rate, and sweat sodium concentration in recreational tropical native runners. METHODS: A total of 102 males and 64 females participated in this study. Participants ran at their self-selected pace for 30-100 min. Age, environmental conditions, running profiles, sweat rates, and sweat sodium data were recorded. Differences in age, running duration, distance and pace, and physiological changes between sexes were analysed. A p-value cut-off of 0.05 depicted statistical significance. RESULTS: Males had lower relative fluid intake (6 ± 6 vs. 8 ± 7 mL·kg-1·h-1, p < 0.05) and greater relative fluid balance deficit (-13 ± 8 mL·kg-1·h-1 vs. -8 ± 7 mL·kg-1·h-1, p < 0.05) than females. Males had higher whole-body sweat rates (1.3 ± 0.5 L·h-1 vs. 0.9 ± 0.3 L·h-1, p < 0.05) than females. Mean rates of sweat sodium loss (54 ± 27 vs. 39 ± 22 mmol·h-1) were higher in males than females (p < 0.05). CONCLUSIONS: The sweat profile and composition in tropical native runners are similar to reported values in the literature. The current fluid replacement guidelines pertaining to volume and electrolyte replacement are applicable to tropical native runners.

The effect of the type of foam pad used in the modified Clinical Test of Sensory Interaction and Balance (mCTSIB) on the accuracy in identifying older adults with fall history.

BACKGROUND: The type of foam pad used in the modified Clinical Test of Sensory Interaction and Balance (mCTSIB) influences the accuracy with which elderly fallers are identified. Two types of foam are commonly used in practice: Airex and Neurocom foam. OBJECTIVE: The aim of this study was to assess the accuracy with which elderly fallers can be identified when the Airex foam and Neurocom foam are used in the mCTSIB. METHODS: One hundred eighty-four elderly participants with a mean age of 69 years were classified into faller and nonfaller groups based on their 12-month fall history. Balance stability was measured under four conditions of the mCTSIB for 120 s each: standing on a floor or a foam pad with their eyes open or eyes closed. The time needed to maintain stability was measured by a stopwatch, and postural sway characteristics were measured using an acceleration-based system. Comparisons between groups were performed by two-way mixed ANOVA. The accuracy of differentiating elderly fallers from nonfallers with different foam types was evaluated using receiver operating characteristic curve (ROC) analysis. The time to maintain stability under four conditions of the mCTSIB (composite score) and under two conditions on the foam (foam score) were used for the ROC analysis. RESULTS: The results showed that the nonfallers required more time to maintain stability and had a smaller sway area than the fallers ( p < 0 . 001 ). The foam led to a larger difference between groups, suggesting the use of foam in examining the risk of falls. The Airex and the Neurocom foam pads led to a large area under the curve (0.93 to 0.95) in identifying elderly fallers and nonfallers when the composite and foam scores were used. A cutoff score of 447/480 s for the composite score and 223/240 s for the foam score yielded a posttest accuracy of 88% to 89%, with a sensitivity of 0.80-0.92 and specificity of 0.88-0.95. CONCLUSION: In conclusion, Airex and Neurocom foam can be used interchangeably with guidance in the mCTSIB, as they led to the accurate identification of elderly fallers among older persons who could walk and live independently in the community.

20-Hydroxyecdysone ameliorates metabolic and cardiovascular dysfunction in high-fat-high-fructose-fed ovariectomized rats.

BACKGROUND: Ecdysteroids are polyhydroxylated steroids present in invertebrates and plants. 20-Hydroxyecdysone (20E) is the most common and the main biologically active compound of ecdysteroids. Previous studies have demonstrated anabolic and metabolic effects of 20E in mammals. However, it is unknown whether 20E has a positive effect on all aspects of cardiometabolic syndrome. The aims of this study were to investigate the favorable effect and possible underlying mechanisms of 20E in a rat model of cardiometabolic syndrome (CMS) induced by a high-calorie diet combined with female sex hormone deprivation. METHODS: 20E (5 mg/kg, 10 mg/kg, or 20 mg/kg) or pioglitazone (PIO) (10 mg/kg) was intragastrically administered to sham-operated Sprague-Dawley female rats and ovariectomized rats fed a high-fat-high-fructose diet (OHFFD) for 8 weeks. The phenotypic characteristics of CMS, including central adiposity, blood pressure, serum lipid profile, glucose tolerance, insulin action on skeletal muscle glucose transport activity and hepatic protein expression, were determined. RESULTS: Some CMS characteristics were improved by 20E treatment. Rats treated with 20E had lower body weight, abdominal fat accumulation than rats treated with vehicle control without changes in total caloric intake and fat-free mass. OHFFD rats exhibited high blood pressure, but 20E-treated rats maintained normal blood pressure with a lower level of low-density lipoprotein (LDL)-cholesterol. Although 20E showed no positive effect on inducing insulin-mediated glucose transport in the skeletal muscle of OHFFD rats, 20E improved whole body glucose homeostasis. Analysis of protein expression in livers from 20E-treated rats revealed significantly increased expression of pAkt Ser473, pFOXO1 Ser256, pAMPKα Thr172, and FGF21. CONCLUSION: 20E treatment can alleviate cardiometabolic disorder caused by a high-fat-high-fructose diet and female sex hormone deprivation. In particular, 20E helps improve whole body insulin sensitivity in OHFFD rats, and the mechanisms that underlie this favorable effect are potentially mediated by the activation of AMPK and FGF21. The present study indicates that 20E could be an alternative therapeutic option for the prevention and alleviation of cardiometabolic syndrome.

Selection of the Better Dual-Timed Up and Go Cognitive Task to Be Used in Patients With Stroke Characterized by Subtraction Operation Difficulties.

Background: The Timed Up and Go Test (TUG) with serial subtraction is commonly used to assess cognitive-dual task performance during walking for fall prediction. Some stroke patients cannot perform number subtraction and it is unclear which cognitive task can be used to substitute for the subtraction task in the TUG test. The aim of this study was to determine the type of cognitive task that produced the highest decrease on both motor and cognitive performances during TUG-dual in stroke patients. Methods: A total of 23 persons with stroke but capable of completing subtraction (ST) and 19 persons with subtraction operation difficulties (SOD) participated. Both groups have a similar age range (ST: 59.3 ± 10.4 years and SOD: 62.0 ± 6.8 years) and stroke onset duration (ST: 44.13 ± 62.29 months and SOD: 42.34 ± 39.69 months). The participants performed TUG without a cognitive task (TUG-single) followed by a cognitive task when seated (cognitive-single). In addition, TUG with a cognitive task (TUG-dual) was performed, with the activity randomly selected from four cognitive tasks, including alternate reciting, auditory working memory, clock task, and phonologic fluency. The main outcome variables-TUG duration measured by OPAL accelerometer and cognitive-dual task effect (DTE)-were analyzed using repeated-measures analyses of variance (ANOVA). Results: The number of correct responses when seated were significantly lower in the SOD as compared to the ST (p < 0.05) during all cognitive tasks, except the phonologic fluency. During TUG-cognitive, TUG duration in the ST was significantly longer for all cognitive tasks compared with TUG-single (p < 0.0001), whereas TUG duration in the SOD was significantly increased only during the phonologic fluency task (p < 0.01). In the ST, there was a significant difference in cognitive DTE between the subtraction and the phonologic fluency tasks (p < 0.01). The highest cognitive cost was found in the subtraction task, whereas the highest cognitive benefit was shown in the phonologic fluency task. No significant cognitive DTE was found among the cognitive tasks in the SOD. Conclusion: For stroke persons with SOD, phonologic fluency is suitable to be used in the TUG-cognitive assessment. In contrast, subtraction (by 3s) is recommended for the assessment of TUG-cognitive in stroke persons who can perform subtraction.

Comparison of measurement properties of three shortened versions of the balance evaluation system test (BESTest) in people with subacute stroke.

OBJECTIVES: To examine the reliability, validity and responsiveness of 3 different short versions of the Balance Evaluation Systems Test (BESTest: S--BESTest, Brief-BESTest and Mini-BESTest) in patients with subacute stroke. DESIGN: A prospective cohort study. PARTICIPANTS: Patients with subacute stroke. METHODS: Patients were assessed using the full BESTest. Scores of 3 short-form BESTests were later extracted. The intra-rater and inter-rater reliability (n = 12) were gathered from 5 raters. Concurrent validity was assessed with the Berg Balance Scale (BBS). Floor/ceiling effect, internal responsiveness and external responsiveness with the BBS (n = 70) were assessed at baseline, 2 weeks and 4 weeks post-rehabilitation. RESULTS AND CONCLUSION: All short-form BESTests demonstrated excellent intra-rater and inter-rater reliability (intraclass correlation coefficient (ICC) = 0.95-0.99) and excellent concurrent validity (r = 0.93-0.96). Unlike the Brief-BESTest and Mini-BESTest, the S-BESTest and BESTest had no significant floor/ceiling effects (< 20%). The standardized response mean of all 4 BESTest versions were large, ranging between 1.19 and 1.57, indicating sufficient internal responsiveness. The area under the curve of the S-BESTest and BESTest were significantly higher than the Brief-BESTest and Mini-BESTest, reflecting better accuracy of the S-BESTest and BESTest in identifying patients with subacute stroke who had balance improvement using the minimal clinically important difference of 6 and 16 points, respectively. These findings suggest that the S-BESTest is a short-form BESTest that is appropriate for assessing balance impairments in patients with subacute stroke.

Rosmarinic acid improves hypertension and skeletal muscle glucose transport in angiotensin II-treated rats.

BACKGROUND: Rosmarinic acid (RA) is a natural pure compound from herbs belonging to the Lamiaceae family, such as rosemary, sage, basil, and mint. The antioxidant, angiotensin-converting enzyme inhibitory, and vasodilatory effects of RA have been revealed. Angiotensin II (ANG II) is a potent agent that generates hypertension and oxidative stress. Hypertension and skeletal muscle insulin resistance are strongly related. The aim of this study was to evaluate the effects of acute and chronic RA treatment on blood pressure and skeletal muscle glucose transport in ANG II-induced hypertensive rats. METHODS: Eight-week-old male Sprague Dawley rats were separated into SHAM and ANG II-infused (250 ng/kg/min) groups. ANG II rats were treated with or without acute or chronic RA at 10, 20, or 40 mg/kg. At the end of the experiment, body weight, liver and heart weights, oral glucose tolerance, skeletal muscle glucose transport activity, and signaling proteins were evaluated. RESULTS: Both acute and chronic RA treatment decreased systolic, diastolic, and mean arterial blood pressure. Only acute RA at 40 mg/kg resulted in a reduction of fasting plasma glucose levels and an induction of skeletal muscle glucose transport activity. These effects might involve increased ERK activity in skeletal muscle. Meanwhile, chronic RA treatment with 10, 20, and 40 mg/kg prevented ANG II-induced hyperglycemia. CONCLUSIONS: Both acute and chronic RA treatment attenuated ANG II-induced cardiometabolic abnormalities in rats. Therefore, RA would be an alternative strategy for improving skeletal muscle glucose transport and protecting against ANG II-induced hypertension and hyperglycemia.

Estrogen and voluntary exercise attenuate cardiometabolic syndrome and hepatic steatosis in ovariectomized rats fed a high-fat high-fructose diet.

The prevalence of cardiometabolic syndrome (CMS) is increased in women after menopause. While hormone replacement therapy has been prescribed to relieve several components of CMS in postmenopausal women, some aspects of cardiometabolic dysfunction cannot be completely restored. The present study examined the effectiveness of estrogen replacement alone and in combination with exercise by voluntary wheel running (VWR) for alleviating the risks of CMS, insulin-mediated skeletal muscle glucose transport, and hepatic fat accumulation in ovariectomized Sprague-Dawley rats fed a high-fat high-fructose diet (OHFFD). We compared a sham-operated group with OHFFD rats that were subdivided into a sedentary, estradiol replacement (E2), and E2 plus VWR for 12 wk. E2 prevented the development of insulin resistance in skeletal muscle glucose transport and decreased hepatic fat accumulation in OHFFD rats. Furthermore, E2 treatment decreased visceral fat mass and low-density lipoprotein (LDL)-cholesterol in OHFFD rats, while VWR further decreased LDL-cholesterol and increased the ratio of high-density lipoprotein-cholesterol to total cholesterol to a greater extent. Although E2 treatment alone did not reduce serum triglyceride levels in OHFFD rats, the combined intervention of E2 and VWR lowered serum triglycerides in E2-treated OHFFD rats. The addition of VWR to E2-treated OHFFD rats led to AMPK activation and upregulation of peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α and PPARδ in skeletal muscle along with increased fatty acid oxidation and suppressed fatty acid synthesis in the liver. Collectively, our findings indicate that, to achieve greater health benefits, physical exercise is required for E2-treated individuals under ovarian hormone deprivation with high-energy consumption.

Role of cardiac mast cells in exercise training-mediated cardiac remodeling in angiotensin II-infused ovariectomized rats.

AIMS: Regular exercise is recommended in postmenopausal women to prevent the development of heart disease, but mechanism underlying the protection is not completely understood. Many studies have suggested that exercise training notably mediated whole body immune and inflammatory functions. Whether exercise training prevents cardiac dysfunction after deprivation of female sex hormones by inhibiting cardiac immune activation is therefore interesting. MAIN METHODS: Nine-week treadmill running program was introduced in sham-operated and ovariectomized rats. In addition, chronic angiotensin II infusion was further challenged to activate pathological cardiac remodeling. Cardiac remodeling in associated with the density and degranulation of cardiac mast cells was then evaluated. KEY FINDINGS: With exogenous angiotensin II-induced hypertension, cardiac hypertrophy with myocardial fibrosis was shown similarly in both sham-operated controls and ovariectomized rats. Although exercise training did not prevent cardiac hypertrophy, myocardial fibrosis was abolished by exercise. While ovariectomy increased both cardiac mast cell density and degranulation percentage, angiotensin II infusion only enhanced mast cell density. Exercise training could not decrease the density of mast cells, but it did normalize the percentage of degranulation in all groups. Correlation analysis suggested that cardiac mast cell activation is inversely associated with cardiomyocyte hypertrophy due to exercise training but is directly correlated to cardiac hypertrophy by angiotensin II infusion. SIGNIFICANCE: Exercise training could attenuate cardiac mast cell hyperactivation induced by either deprivation of female sex hormones or excessive angiotensin II. Additionally, cardiac mast cells could be a solution in the distinction between physiological and pathological hypertrophic development.

Voluntary exercise opposes insulin resistance of skeletal muscle glucose transport during liquid fructose ingestion in rats

We have recently reported that male rats given liquid fructose ingestion exhibit features of cardiometabolic abnormalities including non-obese insulin resistance with impaired insulin signaling transduction in skeletal muscle (Rattanavichit Y et al. Am J Physiol Regul Integr Comp Physiol 311: R1200-R1212, 2016). While exercise can attenuate obesity-related risks of cardiometabolic syndrome, the effectiveness and potential mechanism by which exercise modulates non-obese insulin resistance have not been fully studied. The present investigation evaluated whether regular exercise by voluntary wheel running (VWR) can reduce cardiometabolic risks induced by fructose ingestion. Moreover, the potential cellular adaptations following VWR on key signaling proteins known to influence insulin-induced glucose transport in skeletal muscle of fructose-ingested rats were investigated. Male Sprague-Dawley rats were given either water or liquid fructose (10% wt/vol) without or with access to running wheel for 6 weeks. We demonstrated that VWR restored insulin-stimulated glucose transport in the soleus muscle by improving the functionality of several signaling proteins, including insulin-stimulated IRBetaTyr1158/Tyr1162/Tyr1163 (82%), IRS-1 Tyr989 (112%), Akt Ser473 (56%), AS160 Thr642 (76%), and AS160 Ser588 (82%). These effects were accompanied by lower insulin-stimulated phosphorylation of IRS-1 Ser307 (37%) and JNK Thr183/Tyr185 (49%), without significant changes in expression of proteins in the renin-angiotensin system. Intriguingly, multiple cardiometabolic abnormalities were not observed in fructose-ingested rats with access to VWR. Collectively, this study demonstrates that the development of cardiometabolic abnormalities as well as insulin resistance of skeletal muscle and defective signaling molecules in rats induced by fructose ingestion could be opposed by VWR

Voluntary exercise opposes insulin resistance of skeletal muscle glucose transport during liquid fructose ingestion in rats.

We have recently reported that male rats given liquid fructose ingestion exhibit features of cardiometabolic abnormalities including non-obese insulin resistance with impaired insulin signaling transduction in skeletal muscle (Rattanavichit Y et al. Am J Physiol Regul Integr Comp Physiol 311: R1200-R1212, 2016). While exercise can attenuate obesity-related risks of cardiometabolic syndrome, the effectiveness and potential mechanism by which exercise modulates non-obese insulin resistance have not been fully studied. The present investigation evaluated whether regular exercise by voluntary wheel running (VWR) can reduce cardiometabolic risks induced by fructose ingestion. Moreover, the potential cellular adaptations following VWR on key signaling proteins known to influence insulin-induced glucose transport in skeletal muscle of fructose-ingested rats were investigated. Male Sprague-Dawley rats were given either water or liquid fructose (10% wt/vol) without or with access to running wheel for 6 weeks. We demonstrated that VWR restored insulin-stimulated glucose transport in the soleus muscle by improving the functionality of several signaling proteins, including insulin-stimulated IRß Tyr1158/Tyr1162/Tyr1163 (82%), IRS-1 Tyr989 (112%), Akt Ser473 (56%), AS160 Thr642 (76%), and AS160 Ser588 (82%). These effects were accompanied by lower insulin-stimulated phosphorylation of IRS-1 Ser307 (37%) and JNK Thr183/Tyr185 (49%), without significant changes in expression of proteins in the renin-angiotensin system. Intriguingly, multiple cardiometabolic abnormalities were not observed in fructose-ingested rats with access to VWR. Collectively, this study demonstrates that the development of cardiometabolic abnormalities as well as insulin resistance of skeletal muscle and defective signaling molecules in rats induced by fructose ingestion could be opposed by VWR.

Exercise Protects Against Defective Insulin Signaling and Insulin Resistance of Glucose Transport in Skeletal Muscle of Angiotensin II-Infused Rat.

Objectives: The present study investigated the impact of voluntary exercise on insulin-stimulated glucose transport and the protein expression and phosphorylation status of the signaling molecules known to be involved in the glucose transport process in the soleus muscle as well as other cardiometabolic risks in a rat model with insulin resistance syndrome induced by chronic angiotensin II (ANGII) infusion. Materials and Methods: Male Sprague-Dawley rats were assigned to sedentary or voluntary wheel running (VWR) groups. Following a 6-week period, rats in each group were subdivided and subcutaneously administered either normal saline or ANGII at 100 ng/kg/min for 14 days. Blood pressure, glucose tolerance, insulin-stimulated glucose transport and signaling proteins, including insulin receptor (IR), insulin receptor substrate 1 (IRS-1), Akt, Akt substrate of 160 kDa (AS160), AMPKα, c-Jun NH2-terminal kinase (JNK), p38 MAPK, angiotensin converting enzyme (ACE), ANGII type 1 receptor (AT1R), ACE2, Mas receptor (MasR) and oxidative stress marker in the soleus muscle, were evaluated. Results: Exercise protected against the insulin resistance of glucose transport and defective insulin signaling molecules in the soleus muscle; this effect was associated with a significant increase in AMPK Thr172 (43%) and decreases in oxidative stress marker (31%) and insulin-induced p38 MAPK Thr180/Tyr182 (45%) and SAPK/JNK Thr183/Tyr185 (25%), without significant changes in expression of AT1R, AT2R, ACE, ACE2, and MasR when compared to the sedentary rats given ANGII infusion. At the systemic level, VWR significantly decreased body weight, fat weight, and systolic blood pressure as well as improved serum lipid profiles. Conclusion: Voluntary exercise can alleviate insulin resistance of glucose transport and impaired insulin signaling molecules in the soleus muscle and improve whole-body insulin sensitivity in rats chronically administered with ANGII.

Nonalcoholic fatty liver disease impairs expression of the type II inositol 1,4,5-trisphosphate receptor.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide. It may result in several types of liver problems, including impaired liver regeneration (LR), but the mechanism for this is unknown. Because LR depends on calcium signaling, we examined the effects of NAFLD on expression of the type II inositol 1,4,5-trisphosphate receptor (ITPR2), the principle calcium release channel in hepatocytes. ITPR2 promoter activity was measured in Huh7 and HepG2 cells. ITPR2 and c-Jun protein levels were evaluated in Huh7 cells, in liver tissue from a rat model of NAFLD, and in liver biopsy specimens of patients with simple steatosis and nonalcoholic steatohepatitis (NASH). LR was assessed in wild-type and Itpr2 knockout (Itpr2-/- ) mice following 67% hepatectomy. Cell proliferation was examined in ITPR2-knockout HepG2 cells generated by the CRISPR/Cas9 system. c-Jun dose dependently decreased activity of the human ITPR2 promoter. c-Jun expression was increased and ITPR2 was decreased in fat-loaded Huh7 cells and in livers of rats fed a high-fat, high-fructose diet. Overexpression of c-Jun reduced protein and mRNA expression of ITPR2 in Huh7 cells, whereas knockdown of c-Jun prevented the decrease of ITPR2 in fat-loaded Huh7 cells. ITPR2 expression was decreased and c-Jun was increased in liver biopsies of patients with steatosis and NASH compared to controls. ITPR2-knockout cells exhibited less nuclear calcium signaling and cell proliferation than control cells. LR assessed by Ki-67 and proliferating cell nuclear antigen was markedly decreased in Itpr2-/- mice. Conclusion: Fatty liver induces a c-Jun-mediated decrease in ITPR2 in hepatocytes. This may account for the impaired LR that occurs in NAFLD. (Hepatology 2018;67:560-574).

20-Hydroxyecdysone attenuates cardiac remodeling in spontaneously hypertensive rats.

BACKGROUND: Ecdysteroids, a group of steroid hormones found in insects and many plants, have been shown to prevent various changes in mammalian tissues after female sex hormone deprivation. PURPOSE: To examine whether an ecdysteroid, 20-hydroxyecdysone (20-HE), exhibits regulatory or protective roles in the cardiovascular system. STUDY DESIGN/METHOD: Blood pressure and cardiac function were evaluated in spontaneously hypertensive rats (SHR) during and after daily treatment with 20-HE for six weeks. RESULTS: The progressive increase in systolic blood pressure with age in SHR rats was significantly lower in animals treated with either 5 or 10mg/kg body weight of 20-HE. However, treatment with 20-HE did not diminish the increase in diastolic pressure. Echocardiography after six weeks of treatment demonstrated that the left ventricular chamber of SHR rats treated with 20-HE was smaller than that of SHR controls, while contractility was not affected by 20-HE. Histological images also demonstrated a decrease in cardiomyocyte cross-sectional area in 20-HE treated groups. Interestingly, treatment with 20-HE caused a shift in cardiac myosin heavy chain towards more ß-isoforms. SHR rats treated with 20-HE also exhibited a decrease in seminal vesicular weight and an increase in testicular weight, especially at a dose of 10mg/kg body weight. This finding suggests a possible anti-androgenic effect of 20-HE. CONCLUSION: Our finding reveal that 20-HE has a beneficial effect on reducing blood pressure and consequently preventing dilated cardiac hypertrophy in SHR rats.

Hepatic FGF21 mediates sex differences in high-fat high-fructose diet-induced fatty liver.

The role of gender in the progression of fatty liver due to chronic high-fat high-fructose diet (HFFD) has not been studied. The present investigation assessed whether HFFD induced hepatic perturbations differently between the sexes and examined the potential mechanisms. Male, female, and ovariectomized (OVX) Sprague-Dawley rats were fed either a control diet or HFFD for 12 wk. Indexes of liver damage and hepatic steatosis were analyzed biochemically and histologically together with monitoring changes in hepatic gene and protein expression. HFFD induced a higher degree of hepatic steatosis in females, with significant increases in proteins involved in hepatic lipogenesis, whereas HFFD significantly induced liver injury, inflammation, and oxidative stress only in males. Interestingly, a significant increase in hepatic fibroblast growth factor 21 (FGF21) protein expression was observed in HFFD-fed males but not in HFFD-fed females. Ovarian hormone deprivation by itself led to a significant reduction in FGF21 with hepatic steatosis, and HFFD further aggravated hepatic fat accumulation in OVX rats. Importantly, estrogen replacement restored hepatic FGF21 levels and reduced hepatic steatosis in HFFD-fed OVX rats. Collectively, our results indicate that male rats are more susceptible to HFFD-induced hepatic inflammation and that the mechanism underlying this sex dimorphism is mediated through hepatic FGF21 expression. Our findings reveal sex differences in the development of HFFD-induced fatty liver and indicate the protective role of estrogen against HFFD-induced hepatic steatosis.

Angiotensin II induces differential insulin action in rat skeletal muscle.

Angiotensin II (ANGII) is reportedly involved in the development of skeletal muscle insulin resistance. The present investigation evaluated the effects of two ANGII doses on the phenotypic characteristics of insulin resistance syndrome and insulin action and signaling in rat skeletal muscle. Male Sprague-Dawley rats were infused with either saline (SHAM) or ANGII at a commonly used pressor dose (100 ng/kg/min; ANGII-100) or a higher pressor dose (500 ng/kg/min; ANGII-500) via osmotic minipumps for 14 days. We demonstrated that ANGII-100-infused rats exhibited the phenotypic features of non-obese insulin resistance syndrome, including hypertension, impaired glucose tolerance and insulin resistance of glucose uptake in the soleus muscle, whereas ANGII-500-treated rats exhibited diabetes-like symptoms, such as post-prandial hyperglycemia, impaired insulin secretion and hypertriglyceridemia. At the cellular level, insulin-stimulated glucose uptake in the soleus muscle of the ANGII-100 group was 33% lower (P < 0.05) than that in the SHAM group and was associated with increased insulin-stimulated IRS-1 Ser307 and decreased Akt Ser473 and AS160 Thr642 phosphorylation and GLUT-4 expression. However, ANGII-500 infusion did not induce skeletal muscle insulin resistance or impair insulin signaling elements as initially anticipated. Moreover, we found that insulin-stimulated glucose uptake in the ANGII-500 group was accompanied by the enhanced expression of ACE2 and MasR proteins, which are the key elements in the non-classical pathway of the renin-angiotensin system. Collectively, this study demonstrates for the first time that chronic infusion with these two pressor doses of ANGII induced differential metabolic responses at both the systemic and skeletal muscle levels.