Chronic Delivery of a Thrombospondin-1 Mimetic Decreases Skeletal Muscle Capillarity in Mice

Angiogenesis is an essential process for normal skeletal muscle function. There is a growing body of evidence suggesting that thrombospondin-1 (TSP-1), a potent antiangiogenic protein in tumorigenesis, is an important regulator of both physiological and pathological skeletal muscle angiogenesis. We tested the hypothesis that chronic exposure to a TSP-1 mimetic (ABT-510), which targets the CD36 TSP-1 receptor, would decrease skeletal muscle capillarity as well as alter the balance between positive and negative angiogenic proteins under basal conditions. Osmotic minipumps with either ABT-510 or vehicle (5% dextrose) were implanted subcutaneously in the subscapular region of C57/BL6 mice for 14 days. When compared to the vehicle treated mice, the ABT-510 group had a 20% decrease in capillarity in the superficial region of the gastrocnemius (GA), 11% decrease in the plantaris (PLT), and a 35% decrease in the soleus (SOL). ABT-510 also decreased muscle protein expression of vascular endothelial growth factor (VEGF) in both the GA (−140%) and SOL (−62%); however there was no change in VEGF in the PLT. Serum VEGF was not altered in ABT-510 treated animals. Endogenous TSP-1 protein expression in all muscles remained unaltered. Tunnel staining revealed no difference in muscle apoptosis between ABT-510 and vehicle treated groups. These data provide evidence that the anti-angiogenic effects of TSP-1 are mediated, at least in part, via the CD36 receptor. It also suggests that under physiologic conditions the TSP-1/CD36 axis plays a role in regulating basal skeletal muscle microvessel density

Bariatric Surgery Outcomes in Appalachia Influenced by Surgery Type, Diabetes, and Depression

Background Most effective treatment for morbid obesity and its comorbidities is bariatric surgery. However, research is limited on weight loss and associated outcomes among patients in Appalachia. The objective of this study was to examine demographic and comorbidity influence on surgical outcomes of this population including age, sex, race, state of residence, education, marital status, body mass index (BMI kg/m2), excess body weight (EBW), percent excess weight loss (%EWL), blood pressure, diagnosed depression, diagnosed type 2 diabetes (T2D), Beck Depression Inventory-II (BDI-II), and laboratory values (i.e., hemoglobin A1c). Methods A retrospective electronic medical record (EMR) data extraction was performed on N = 582 patients receiving bariatric surgery (laparoscopic Roux-en-Y gastric bypass [RYGB] and laparoscopic sleeve gastrectomy [SG]) between 10/2013 and 2/2017. Results Patient population was 92.5% Caucasian, 79.3% female, 62.8% married, 45 ± 11.1 years, 75.8% received RYGB, and 24.2% received SG. Average %EWL from baseline to 1-year follow-up was 68.5 ± 18.4% (n = 224). In final descriptive models, surgery type, diagnosed T2D, HbA1c, and depressive symptoms were significant covariates associated with lower %EWL. Conclusions Findings suggest patients completing surgery within an Appalachian region have successful surgical outcomes at 1-year post-surgery, as indicated by significant reductions of \u3e 50% EWL, regardless of other covariates. Results suggest that bariatric programs should consider paying special consideration to patients with T2D or depressive symptoms to improve outcomes. Results have potential to inform future prospective studies and aid in guiding specific interventions tailored to address needs of this unique population

Inflammatory cytokine response to exercise in alpha-1-antitrypsin deficient COPD patients ‘on’ or ‘off’ augmentation therapy

Background: There is still limited information on systemic inflammation in alpha-1-antitrypsin-deficient (AATD) COPD patients and what effect alpha-1-antitrypsin augmentation therapy and/or exercise might have on circulating inflammatory cytokines. We hypothesized that AATD COPD patients on augmentation therapy (AATD + AUG) would have lower circulating and skeletal muscle inflammatory cytokines compared to AATD COPD patients not receiving augmentation therapy (AATD-AUG) and/or the typical non-AATD (COPD) patient. We also hypothesized that cytokine response to exercise would be lower in AATD + AUG compared to AATD-AUG or COPD subjects. Methods: Arterial and femoral venous concentration and skeletal muscle expression of TNFα, IL-6, IL-1β and CRP were measured at rest, during and up to 4-hours after 50% maximal 1-hour knee extensor exercise in all COPD patient groups, including 2 additional groups (i.e. AATD with normal lung function, and healthy age-/activity-matched controls). Results: Circulating CRP was higher in AATD + AUG (4.7 ± 1.6 mg/dL) and AATD-AUG (3.3 ± 1.2 mg/dL) compared to healthy controls (1.5 ± 0.3 mg/dL, p < 0.05), but lower in AATD compared to non-AATD-COPD patients (6.1 ± 2.6 mg/dL, p < 0.05). TNFα, IL-6 and IL-1β were significantly increased by 1.7-, 1.7-, and 4.7-fold, respectively, in non-AATD COPD compared to AATD COPD (p < 0.05), and 1.3-, 1.7-, and 2.2-fold, respectively, compared to healthy subjects (p < 0.05). Skeletal muscle TNFα was on average 3–4 fold greater in AATD-AUG compared to the other groups (p < 0.05). Exercise showed no effect on these cytokines in any of our patient groups. Conclusion: These data show that AATD COPD patients do not experience the same chronic systemic inflammation and exhibit reduced inflammation compared to non-AATD COPD patients. Augmentation therapy may help to improve muscle efflux of TNFα and reduce muscle TNFα concentration, but showed no effect on IL-6, IL-1β or CRP

Effect of chronic stress on running wheel activity in mice

Acute and chronic stress have been reported to have differing effects on physical activity in rodents, but no study has examined a chronic stress protocol that incorporates stressors often experienced by rodents throughout a day. To examine this, the effects of the Unpredict- able Chronic Mild Stress (UCMS) protocol on voluntary running wheel activity at multiple time points, and/or in response to acute removal of chronic stress was determined. Twenty male Balb/c mice were given access and accustomed to running wheels for 4 weeks, after which they were randomized into 2 groups; exercise (EX, n = 10) and exercise with chronic stress using a modified UCMS protocol for 7 hours/day (8:00 a.m.-3:00p.m.), 5 days/week for 8 weeks (EXS, n = 10). All mice were given access to running wheels from approximately 3:30 p.m. to 7:30 a.m. during the weekday, however during weekends mice had full-time access to running wheels (a time period of no stress for the EXS group). Daily wheel running distance and time were recorded. The average running distance, running time, and work each week- day was significantly lower in EXS compared to EX mice, however, the largest effect was seen during week one. Voluntary wheel running deceased in all mice with increasing age; the pattern of decline appeared to be similar between groups. During the weekend (when no stress was applied), EXS maintained higher distance compared to EX, as well as higher daily distance, time, and work compared to their weekday values. These results indicate that mild chronic stress reduces total spontaneous wheel running in mice during the first week of the daily stress induction and maintains this reduced level for up to 8 consecutive weeks. How- ever, following five days of UCMS, voluntary running wheel activity rebounds within 2–3 days

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

The 2010 USDA Dietary Guidelines for Americans (DGA) recommends a diet largely composed of fruit and vegetables. Consuming a diet high in fruit and vegetables and low in refined carbohydrates and saturated fat may reduce an individual’s risk for type 2 diabetes, nonalcoholic fatty liver disease, low-grade chronic inflammation, and metabolic syndrome (MetS). Several recent studies have implicated the bioactive sphingolipid ceramide as an associative and causative biomarker for the development of these conditions. Considering that the intake of fruit and vegetables is frequently inadequate in young adults, we performed a pilot investigation to assess the efficacy of a free-living fruit and vegetable intervention on overall metabolic health, circulating ceramide supply, and inflammatory status in young adults. We discovered that adoption of the recommended DGA for fruit and vegetable intake for 8 weeks decreased waist circumference, systolic blood pressure, and circulating cholesterol. Lipidomics analysis revealed that nutritional intervention can lower circulating ceramides, including C24:0 ceramide, a known inhibitor of insulin signaling. Unexpectedly, we observed an increase in C16:0 ceramide, suggesting that this form of ceramide in circulation is not associated with metabolic disease in humans. We also observed an improved inflammatory status with enhanced fruit and vegetable intake that was correlated with ceramide concentrations. These data suggest that adopting the recommended DGA is associated with a reduction of many, but not all, ceramide species and may help to prevent or mitigate MetS. Future research needs to assess whether the ceramide-lowering ability of nutritional intervention is associated with reduced risk of developing metabolic disease

Angiotensin II Evokes Angiogenic Signals within Skeletal Muscle through Co-ordinated Effects on Skeletal Myocytes and Endothelial Cells

Skeletal muscle overload induces the expression of angiogenic factors such as vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-2, leading to new capillary growth. We found that the overload-induced increase in angiogenesis, as well as increases in VEGF, MMP-2 and MT1-MMP transcripts were abrogated in muscle VEGF KO mice, highlighting the critical role of myocyte-derived VEGF in controlling this process. The upstream mediators that contribute to overload-induced expression of VEGF have yet to be ascertained. We found that muscle overload increased angiotensinogen expression, a precursor of angiotensin (Ang) II, and that Ang II signaling played an important role in basal VEGF production in C2C12 cells. Furthermore, matrix-bound VEGF released from myoblasts induced the activation of endothelial cells, as evidenced by elevated endothelial cell phospho-p38 levels. We also found that exogenous Ang II elevates VEGF expression, as well as MMP-2 transcript levels in C2C12 myotubes. Interestingly, these responses also were observed in skeletal muscle endothelial cells in response to Ang II treatment, indicating that these cells also can respond directly to the stimulus. The involvement of Ang II in muscle overload-induced angiogenesis was assessed. We found that blockade of AT1R-dependent Ang II signaling using losartan did not attenuate capillary growth. Surprisingly, increased levels of VEGF protein were detected in overloaded muscle from losartan-treated rats. Similarly, we observed elevated VEGF production in cultured endothelial cells treated with losartan alone or in combination with Ang II. These studies conclusively establish the requirement for muscle derived VEGF in overload-induced angiogenesis and highlight a role for Ang II in basal VEGF production in skeletal muscle. However, while Ang II signaling is activated following overload and plays a role in muscle VEGF production, inhibition of this pathway is not sufficient to halt overload-induced angiogenesis, indicating that AT1-independent signals maintain VEGF production in losartan-treated muscle

Educational intervention improves fruit and vegetable intake in young adults with metabolic syndrome components

The FRUVEDomics study investigates the effect of a diet intervention focused on increasing fruit and vegetable intake on the gut microbiome and cardiovascular health of young adults with/at risk for metabolic syndrome(MetS). It was hypothesized that the recommended diet would result in metabolic and gut microbiome changes. The 9-week dietary intervention adhered to the US Department of Agriculture Dietary Guidelines for Americansand focused on increasing fruit and vegetable intake to equal half of the diet. Seventeen eligible young adults with/or at high risk of MetS consented and completed preintervention and postintervention measurements, including anthropometric, body composition, cardiovascular, complete blood lipid panel, and collection of stool sample for microbial analysis. Participants attended weekly consultations to assess food logs, food receipts, and adherence to the diet. Following intention-to-treat guidelines, all 17 individuals were included in the dietary, clinical, and anthropometric analysis. Fruit and vegetable intake increased from 1.6 to 3.4 cups of fruits and vegetables (P \u3c .001) daily. Total fiber (P = .02) and insoluble fiber (P \u3c .0001) also increased. Clinical laboratory changes included an increase in sodium (P = .0006) and low-density lipoprotein cholesterol (P = .04). In the fecal microbiome, Erysipelotrichaceae (phylum Firmicutes) decreased (log2 fold change: −1.78, P = .01) and Caulobacteraceae (phylum Proteobacteria) increased (log2 fold change = 1.07, P = .01). Implementing a free-living 9-week diet, with intensive education and accountability, gave young adults at high risk for/or diagnosed with MetS the knowledge, skills, and feedback to improve diet. To yield greater impact, a longer diet intervention may be needed in this population

Monetary Cost of the MyPlate Diet in Young Adults: Higher Expenses Associated with Increased Fruit and Vegetable Consumption

Background. Cost is a commonly reported barrier to healthy eating. This is a secondary research analysis designed to examine the food expenditures of young adults on a university campus following the United States Department of Agriculture (USDA) MyPlate guidelines for fruits and vegetables. Methods. Meal receipts and dietary intake were recorded weekly. Anthropometrics and clinical assessments were recorded before intervention. Researchers rated compliance based on the participant’s dietary food log, receipt matching, food pictures, and reports during weekly 1-hour consultations. Results. Fifty-three young adults (18–30 years old) at-risk of, or diagnosed with, metabolic syndrome (MetS) were enrolled in the study, with 10 excluded (n = 43) from analyses due to enrollment in a fixed cost university campus dining meal plan. A two sample t-test assessed differences in food costs and regression analysis determined associations between food cost and diet compliance while controlling for confounding factors of age, sex, and body mass index (BMI). Diet compliant subjects (n = 38) had higher weekly food cost at $95.73 compared to noncompliant subjects (n = 5) who spent$66.24 (). A regression analysis controlling for age, sex, BMI, and geographical region also indicated cost differences based on diet compliance (). Conclusion. Results indicate an ∼$29.00 per week increase in food cost when eating the recommended amount of fruit and vegetables. These findings can contribute to research incentive design, program planning cost, and determining effective interventions to improve diet in this population

Exercise Training Prevents the Perivascular Adipose Tissue-induced Aortic Dysfunction with Metabolic Syndrome

The aim of the study was to determine the effects of exercise training on improving the thoracic perivascularadipose tissue (tPVAT) phenotype (inflammation, oxidative stress, and proteasome function) in metabolic syn-drome and its subsequent actions on aortic function.Methods:Lean and obese (model of metabolic syndrome) Zucker rats (n=8/group) underwent 8-weeks ofcontrol conditions or treadmill exercise (70% of max speed, 1 h/day, 5 days/week). At the end of the inter-vention, the tPVAT was removed and conditioned media was made. The cleaned aorta was attached to a forcetransducer to assess endothelium-dependent and independent dilation in the presence or absence of tPVAT-conditioned media. tPVAT gene expression, inflammatory /oxidative phenotype, and proteasome function wereassessed.Results:The mainfindings were that Ex induced: (1) a beige-like, anti-inflammatory tPVAT phenotype; (2) agreater abundance of•NO in tPVAT; (3) a reduction in tPVAT oxidant production; and (4) an improved tPVATproteasome function. Regarding aortic function, endothelium-dependent dilation was greater in exercised leanand obese groups vs. controls (p \u3c 0.05). Lean control tPVAT improved aortic relaxation, whereas obese controltPVAT decreased aortic relaxation. In contrast, the obese Ex-tPVAT increased aortic dilation, whereas the leanEx-tPVAT did not affect aortic dilation.Conclusion:Overall, exercise had the most dramatic impact on the obese tPVAT reflecting a change towards anenvironment with less oxidant load, less inflammation and improved proteasome function. Such beneficialchanges to the tPVAT micro-environment with exercise likely played a significant role in mediating the im-provement in aortic function in metabolic syndrome following 8 weeks of exercise

Hypoxic Preconditioning Attenuates Reoxygenation-Induced Skeletal Muscle Dysfunction in Aged Pulmonary TNF-α Overexpressing Mice

Aim: Skeletal muscle subjected to hypoxia followed by reoxygenation is susceptible to injury and subsequent muscle function decline. This phenomenon can be observed in the diaphragm during strenuous exercise or in pulmonary diseases such as chronic obstructive pulmonary diseases (COPD). Previous studies have shown that PO2 cycling or hypoxic preconditioning (HPC), as it can also be referred to as, protects muscle function via mechanisms involving reactive oxygen species (ROS). However, this HPC protection has not been fully elucidated in aged pulmonary TNF-α overexpressing (Tg+) mice (a COPD-like model). We hypothesize that HPC can exert protection on the diaphragms of Tg+ mice during reoxygenation through pathways involving ROS/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/extracellular signal regulated kinase (ERK), as well as the downstream activation of mitochondrial ATP-sensitive potassium channel (mitoKATP) and inhibition of mitochondrial permeability transition pore (mPTP).Methods: Isolated Tg+ diaphragm muscle strips were pre-treated with inhibitors for ROS, PI3K, Akt, ERK, or a combination of mitoKATP inhibitor and mPTP opener, respectively, prior to HPC. Another two groups of muscles were treated with either mitoKATP activator or mPTP inhibitor without HPC. Muscles were treated with 30-min hypoxia, followed by 15-min reoxygenation. Data were analyzed by multi-way ANOVA and expressed as means ± SE.Results: Muscle treated with HPC showed improved muscle function during reoxygenation (n = 5, p &lt; 0.01). Inhibition of ROS, PI3K, Akt, or ERK abolished the protective effect of HPC. Simultaneous inhibition of mitoKATP and activation of mPTP also diminished HPC effects. By contrast, either the opening of mitoKATP channel or the closure of mPTP provided a similar protective effect to HPC by alleviating muscle function decline, suggesting that mitochondria play a role in HPC initiation (n = 5; p &lt; 0.05).Conclusion: Hypoxic preconditioning may protect respiratory skeletal muscle function in Tg+ mice during reoxygenation through redox-sensitive signaling cascades and regulations of mitochondrial channels