Skeletal Muscle Adipose Research Articles

Skeletal muscle mass is associated with toxicity, treatment tolerability, and additional or subsequent therapies in patients with hepatocellular carcinoma receiving sorafenib treatment.

Background and AimSeveral reports have demonstrated that skeletal muscle mass influences mortality in patients with hepatocellular carcinoma (HCC) receiving sorafenib treatment; however, there is still controversy with regard to whether skeletal muscle and adipose tissue are associated with the prognosis in HCC patients. We examined the relationship between body composition and prognosis in HCC patients.MethodsWe retrospectively analyzed 82 patients with unresectable HCC receiving sorafenib treatment. The skeletal muscle area and adipose tissue area were measured by computed tomography. Patients with low skeletal muscle index (male ≤36.2 cm2/m2, female ≤29.6 cm2/m2) and high visceral to subcutaneous adipose tissue area ratio (VSR) (male ≥ 1.33, female ≥ 0.93) were diagnosed as low skeletal muscle mass (LSMM) and high VSR, respectively.ResultsA total of 16 and 34 patients were classified as LSMM and high VSR, respectively. LSMM patients frequently experienced serious adverse events (SAEs) and thus had a shorter duration of sorafenib treatment than non‐LSMM patients. High VSR was a significant factor for progression‐free survival. LSMM patients less frequently received additional/subsequent therapies combined with sorafenib than non‐LSMM patients. Multivariate Cox hazard analysis demonstrated that LSMM was a significant factor for the duration of sorafenib treatment. The treatment duration and receiving of additional/subsequent therapies were significantly associated with overall survival (OS) but not with LSMM or high VSR.ConclusionLSMM was associated with the frequency of SAEs, treatment tolerability, and treatment duration. LSMM patients were less likely to receive additional/subsequent therapies than non‐LSMM patients. Thus, LSMM could identify a subgroup of patients with poor OS.

Pharmacological AMPK activation induces transcriptional responses congruent to exercise in skeletal and cardiac muscle, adipose tissues and liver.

Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise that occur within skeletal muscle and other organs. There is interest in discovering a pharmacologic exercise mimetic that could imbue wellness and alleviate disease burden. However, the molecular physiology by which exercise signals the transcriptional response is highly complex, making it challenging to identify a single target for pharmacological mimicry. The current studies evaluated the transcriptome responses in skeletal muscle, heart, liver, and white and brown adipose to novel small molecule activators of AMPK (pan-activators for all AMPK isoforms) compared to that of exercise. A striking level of congruence between exercise and pharmacological AMPK activation was observed across the induced transcriptome of these five tissues. However, differences in acute metabolic response between exercise and pharmacologic AMPK activation were observed, notably for acute glycogen balances and related to the energy expenditure induced by exercise but not pharmacologic AMPK activation. Nevertheless, intervention with repeated daily administration of short-acting activation of AMPK was found to mitigate hyperglycemia and hyperinsulinemia in four rodent models of metabolic disease and without the cardiac glycogen accretion noted with sustained pharmacologic AMPK activation. These findings affirm that activation of AMPK is a key node governing exercise mediated transcription and is an attractive target as an exercise mimetic.

Vaspin promotes insulin sensitivity of elderly muscle and is upregulated in obesity.

Adipokines have emerged as central mediators of insulin sensitivity and metabolism, in part due to the known association of obesity with metabolic syndrome disorders such as type 2 diabetes. Recent studies in rodents have identified the novel adipokine vaspin, as playing a protective role in inflammatory metabolic diseases by functioning to promote insulin sensitivity during metabolic stress. However, at present the skeletal muscle and adipose tissue expression of vaspin in humans is poorly characterised. Furthermore, the functional role of vaspin in skeletal muscle insulin sensitivity has not been studied. Since skeletal muscle is the major tissue for insulin-stimulated glucose uptake understanding the functional role of vaspin in human muscle insulin signalling is critical in determining its role in glucose homeostasis. The objective of this study was to profile the skeletal muscle and subcutaneous adipose tissue expression of vaspin in humans of varying adiposity and to determine the functional role of vaspin in mediating insulin signalling and glucose uptake in human skeletal muscle. Our data shows that vaspin is secreted from both human subcutaneous adipose tissue and skeletal muscle, and is more highly expressed in obese older individuals compared to lean older individuals. Furthermore, we demonstrate that vaspin induces activation of the PI3K/AKT axis, independent of insulin receptor activation, promotes GLUT4 expression and translocation and sensitises older obese human skeletal muscle to insulin-mediated glucose uptake.

Quantification of fat and skeletal muscle tissue at abdominal computed tomography: associations between single-slice measurements and total compartment volumes

Body composition is of great prognostic value in several severe diseases, including different types of cancer as well as cardiometabolic disorders. We aimed to investigate the correlations of skeletal muscle mass and abdominal adipose tissue compartments between volumetric and single-slice measurements to study the usefulness of several anatomical landmarks for estimation of total compartment volumes using abdominal CT-scans. In this retrospective study volumetric quantifications of paraspinal skeletal muscles (SM) and adipose tissue compartments (visceral adipose tissue, VAT; subcutaneous adipose tissue, SAT) were performed in 50 consecutive patients (26 male; mean age, 63 ± 15years) who underwent abdominal multislice-CT for diagnostic purposes using an in-house software. Associations between total volumes of SM, VAT, and SAT with single-slice measurements at eight predefined anatomical landmarks (median intervertebral disk spaces T12/L1 to L5/S1; level of the umbilicus (U); level of the radix of the superior mesenteric artery (SMA)) were studied using correlation coefficients. Statistical analysis revealed a strong association between single-slice measurements of adipose tissue compartments with total VAT and SAT volume (VAT: all r > 0.89, P < 0.001; SAT: all r > 0.95, P < 0.001). The strongest associations with total SM volume were found for single-slice measurements obtained at L3/4 (r = 0.94, P < 0.001) and were further improved by normalization to height (r = 0.98, P < 0.001). Single-slice measurements of SM, VAT, and SAT at several anatomical landmarks are strongly associated with total compartment volumes and therefore allow for easy and simultaneous assessment of skeletal muscle mass and adipose tissue compartment volumes.

Wnt Pathway Inhibitor DKK1: A Potential Novel Biomarker for Adiposity

Emerging evidence indicates that ectopic skeletal muscle adiposity may be a risk factor for type 2 diabetes (T2D), especially in persons of African ancestry. In vitro studies suggest that a Wnt pathway inhibitor, Dickkopf-related protein 1 (DKK1), plays a role in adiposity regulation and could be a biomarker for adiposity in humans. The objective of this study was to test whether serum DKK1 levels relate to adiposity measures in a cohort from an African ancestry population at high risk for T2D. Fasting serum DKK1 was measured in a sample of 159 men of African ancestry aged ≥40 years (mean age ± SD, 63.5 ± 8.2 years; mean body mass index, 27.8 ± 4.5 kg/m2). Anthropometrics included total-body and trunk adiposity measured by dual-energy x-ray absorptiometry and lower-leg skeletal muscle density measured by CT [which reflects the intramuscular adiposity content (mg/cm3)]. Serum DKK1 was positively correlated with BMI (r = 0.20; P = 0.01), waist circumference (r = 0.15; P = 0.046), DXA total-body adiposity (r = 0.24; P = 0.003), and DXA trunk adiposity (r = 0.21; P = 0.009), independent of age and height. In addition, serum DKK1 was inversely correlated with skeletal muscle density (r = −0.25; P = 0.002), independent of age, BMI, and calf muscle area. No significant correlation was found between serum DKK1 and fasting serum glucose or insulin levels or insulin resistance estimated by homeostasis model assessment. These findings suggest that higher levels of serum DKK1 may be associated with greater overall, central, and ectopic skeletal muscle adiposity. Further studies are needed to unravel the potential role of DKK1 in the regulation of adiposity in humans.

Anti-diabetic activity of canophyllol from Cratoxylum cochinchinense (Lour.) Blume in type 2 diabetic mice by activation of AMP-activated kinase and regulation of PPARγ.

In the present study, the potential anti-diabetic activity of canophyllol (CNPL) and its mechanisms were investigated in vitro and in vivo. CNPL is a predominant friedelane-type triterpene extracted from young leaves of Cratoxylum cochinchinense ("Huang Niu Tea"). In vitro, CNPL increased GLUT4 translation in a L6-myotube model to 2.60-fold, and glucose uptake to 1.71-fold levels relative to untreated L6 myotubes. Moreover, compound C, an inhibitor of AMP-activated protein kinase (AMPK), completely suppressed the CNPL-induced GLUT4 translocation. In vivo, serum insulin levels, hyperglycemia, as well as other blood indexes of the KK-Ay diabetic mice were improved by a four-week oral administration of CNPL. Examination of its possible anti-diabetic mechanism showed that CNPL promoted the expression of p-AMPKα and GLUT4 in L6 myotubes. In KK-Ay mice treated with CNPL, GLUT4 expression was increased in skeletal muscle and white adipose tissue, and the levels of p-AMPKα were increased in the liver, skeletal muscle and white adipose tissue. Moreover, CNPL stimulated the expression of PPARγ to decrease and inhibited the activity of ACC by stimulating its phosphorylation in both liver and white adipose tissue, thereby indicating that CNPL also improved lipid metabolism disorders. Altogether, these results show that CNPL may improve glucose tolerance, reduce hyperglycemia, normalize insulin secretion, and ameliorate lipid metabolism disorders. The diverse anti-diabetic effects of CNPL may be attributed to the regulation of GLUT4, PPARγ, AMPK phosphorylation and ACC phosphorylation.

Changes in Metabolism, Mitochondrial Function, and Oxidative Stress Between Female Rats Under Nonreproductive and 3 Reproductive Conditions.

Women who do not lactate display increased incidence of obesity, type II diabetes, and cancer. Stuebe and Rich-Edwards proposed that these effects occur because physiological changes that ensue during pregnancy are not reversed without lactation. To empirically test this hypothesis, we compared markers of metabolism, mitochondrial function, and oxidative stress between 4 groups of Sprague-Dawley rats: (1) nonreproductive (NR) rats, (2) rats killed at day 20 of gestation, (3) rats that gave birth but were not allowed to suckle their pups (nonlactating), and (4) rats that suckled their young for 14 days. Nonlactating females displayed higher body fat compared to all other groups. Peroxisome proliferator-activated receptor δ (PPARδ) in skeletal muscle and white adipose tissue of nonlactating rats was lower than the other groups. The PPARδ is associated with lipid metabolism suggesting that the higher fat mass in nonlactating females was not associated with the retention of a physiological state that was set during pregnancy but instead an independent drop in PPARδ. Relative mitochondrial respiratory function and complex activity in the liver and skeletal muscle of nonlactating mice were not predictive of higher body mass, and measures of oxidative stress displayed minimal variation between groups.

Changes in body weight, skeletal muscle and adipose tissue after gastrectomy: a comparison between proximal gastrectomy and total gastrectomy

Proximal gastrectomy (PG) offers a well-preserved digestive function after surgery, which may result in a better nutritional outcome in comparison to total gastrectomy (TG). The aim of this study was to clarify the advantage of PG over TG by evaluating the longitudinal changes in body weight (BW) and body composition after surgery. A total of 112 patients undergoing PG with a reconstruction preserving food passage through the duodenum (n = 39) or TG with a reconstruction bypassing the duodenum (n = 73) for clinical stage IA gastric cancer were included. Changes in BW, psoas muscle and subcutaneous (SAT) and visceral adipose tissue were assessed before surgery, and at 1 and 3 years after surgery and were compared between the two groups. BW and SAT decreased significantly in both groups, but the rate of reduction was significantly lower in the PG group (P < 0.001 and P < 0.001, respectively). There were no significant differences between the groups with regard to skeletal muscle or visceral adipose tissue (P = 0.110 and 0.710, respectively), although they both significantly decreased throughout the course of the study. The losses of BW and SAT were significantly smaller in the PG group. PG may be superior to TG in preserving BW and SAT in patients with clinical stage IA gastric cancer.

Protective effects of Bacillus probiotics against high-fat diet-induced metabolic disorders in mice.

Recently, modulation of gut microbiota by probiotics treatment has been emerged as a promising strategy for treatment of metabolic disorders. Apart from lactic acid bacteria, Bacillus species (Bacillus spp.) have also been paid attention as potential probiotics, but nevertheless, the molecular mechanisms for their protective effect against metabolic dysfunction remain to be elucidated. In this study, we demonstrate that a probiotic mixture composed of 5 different Bacillus spp. protects mice from high-fat diet (HFD)-induced obesity, insulin resistance and non-alcoholic fatty liver disease (NAFLD). Probiotic Bacillus treatment substantially attenuated body weight gain and enhanced glucose tolerance by sensitizing insulin action in skeletal muscle and epididymal adipose tissue (EAT) of HFD-fed mice. Bacillus-treated HFD-fed mice also exhibited significantly suppressed chronic inflammation in the liver, EAT and skeletal muscle, which was observed to be associated with reduced HFD-induced intestinal permeability and enhanced adiponectin production. Additionally, Bacillus treatment significantly reversed HFD-induced hepatic steatosis. In Bacillus-treated mice, hepatic expression of lipid oxidative genes was significantly increased, and lipid accumulation in subcutaneous and mesenteric adipose tissues were significantly decreased, commensurate with down-regulated expression of genes involved in lipid uptake and lipogenesis. Although, in Bacillus-treated mice, significant alterations in gut microbiota composition was not observed, the enhanced expression of tight junction-associated proteins showed a possibility of improving gut barrier function by Bacillus treatment. Our findings provide possible explanations how Bacillus probiotics protect diet-induced obese mice against metabolic disorders, identifying the treatment of probiotic Bacillus as a potential therapeutic approach.

The Effects of Aging on Rho-Kinase and Insulin Signaling in Skeletal Muscle and White Adipose Tissue of Rats.

The insulin receptor substrate 1 regulates insulin-mediated glucose uptake and is a target of Rho-kinase (Rock); however, the relationship between age-related insulin resistance and Rock signaling specifically in skeletal muscle and adipose tissue is unknown. We evaluated the content and activity of Rock in C2C12 myotubes, and in skeletal muscle and white adipose tissue (WAT) from two rodent models that differ in their patterns of body fat accumulation during aging (Wistar and Fischer 344 rats). Body fat gain in the Wistar rats was greater than in Fischer rats and only Wistar rats had impairment of whole-body insulin sensitivity. Rock activity and insulin signaling were impaired in skeletal muscle in both rat models, but only middle-aged Wistar rats had higher Rock activity in WAT. These data are consistent with a positive role of Rock in regulating insulin signaling in both skeletal muscle and its negative role in the adipose tissue, suggesting that Rock activity in adipose tissue is important in age-related insulin resistance.

The Effects of Exercise Regimens on Irisin Levels in Obese Rats Model: Comparing High-Intensity Intermittent with Continuous Moderate-Intensity Training.

Background Recently, high-intensity intermittent training (HIIT) appears to have the same beneficial effects or even superior to those of continuous moderate-intensity training (CMIT) on body fat mass reduction. Exercise may induce myokine secretion such as irisin, which plays a role as a mediator of beiging process, and thus might contribute as treatment of obesity. However, the effects of those exercise formulas on irisin level changes as beiging agent are not known. In addition, metabolic states may affect the irisin responses to those exercise formulas. Therefore, this study was aimed to determine the different effects of exercises using HIIT and CMIT on circulating and tissue irisin levels in normal and abnormal metabolic conditions (obese). Methods Sixteen male Sprague-Dawley rats (8 weeks of age) were randomized to 4 groups according to training regimens (HIIT and CMIT) and metabolic conditions (normal and abnormal/obese). The groups are (1) HIIT on normal metabolic (n=4), (2) CMIT on normal metabolic (n=4), (3) HIIT on abnormal metabolic (n=4), and (4) CMIT on abnormal metabolic (n=4). Abnormal metabolic condition was induced with high fat diet (19% fat) for 8 weeks in obese rats. Irisin levels in serum, skeletal muscle, and white adipose tissue were evaluated by ELISA. Results Serum irisin levels were shown significantly higher in normal metabolic compared to abnormal metabolic condition (P<0.001). The effect of interaction between metabolic condition and exercise formula was found (P<0.01) on adipose irisin levels. The effect of HIIT was shown significantly more effective on adipose irisin levels, compared with CMIT in abnormal metabolic conditions. However, no significant differences of skeletal muscle irisin levels were found in both normal and abnormal metabolic subjects (P>0.05). Regarding exercise formula, no different effects were found between HIIT and CMIT on skeletal muscle irisin levels in both metabolic conditions (P>0.05). The similar findings were observed in serum irisin levels (P>0.05). Conclusions The exercise effects in abnormal metabolic condition might be more adaptable in maintaining the irisin levels in skeletal muscle and induce the irisin uptake from circulation into adipose tissue. In addition, HIIT might be more involved to induce irisin uptake into adipose tissue; thus it might have the significant role in beiging process. However, further research about how the HIIT formula affects the regulation mechanisms of irisin uptake into adipose tissue is still warranted.

Sarcopenic obesity derived from PET/CT predicts mortality in lymphoma patients undergoing hematopoietic stem cell transplantation

BackgroundSarcopenic Obesity (SO) is associated with worse survival among chemotherapy recipients. Research on SO is scarce among lymphoma patients receiving Hematopoietic Stem Cell Transplantation (HSCT). Aimassess prevalence of SO pre-HSCT (T0) and 3 months post-HSCT (T1) in lymphoma patients and determine the power of SO at T0 and T1 in predicting survival. MethodsConsecutive patients (age ≥16 years) having B and T cell lymphoma who underwent SCT and who had PET/CT scan pre-SCT and 3 months post SCT were included in the study. A cross sectional image was analyzed at the level of the 3rd Lumber Vertebrae to assess body composition parameters. Results93 patients [mean age: 38 (range: 17–70 years), 52 (55.9%) males, 45 (48%) Hodgkin and 48 (52%) Non-Hodgkin lymphoma, 81 (87%) autologous and 12 (13%) allogeneic SCT)] met the inclusion criteria. From T0 to T1, Sarcopenia rates increased (27% at T0 to 38% at T1, p = 0.013), Visceral adiposity decreased (46% at T0 to 30% at T1, p = 0.03) and SO decreased (42% at T0 to 20% at T1, p < 0.01). Length of stay, overall survival and progression free survival were significantly better in patients without sarcopenic obesity at T1. Cox-regression revealed SO at T1 was a risk factor for mortality [Adjusted Hazards Ratio = 8.2 (95% Confidence Interval: 1.9–36.2)]. ConclusionSarcopenic obesity, prevalent in 42% of patients pre-HSCT, decreased 3 months post HSCT as lymphoma patients lost skeletal muscle and visceral adipose tissues. SO at T1 was the most impactful risk factor for mortality.

Current technologies in body composition assessment: advantages and disadvantages.

The interest in non-invasive methods of body composition assessment is on the rise in health care, especially because of its association with clinical outcomes. Technology has revolutionized our understanding of body composition abnormalities, clinical prognostication, and disease follow-up, but translation to bedside is limited, especially in terms of cost effectiveness. Computed tomography gained increased attention in cancer and sarcopenia studies, for instance. Other methods also have interesting features and applications, including bedside ultrasonography, bioelectrical impedance analysis, and dual x-ray absorptiometry. Compelling evidence indicates these methods can be used to accurately and precisely measure skeletal muscle mass, adipose tissue, and edema; diagnose malnutrition-related diseases; and aid in determining prognoses. To apply this technology properly, it is important to understand the advantages and disadvantages of each technique in specific situations of interest. This review introduces concepts and reference studies published in the scientific literature about these techniques and describes important limitations and considerations necessary to incorporate these methods into clinical practice.

CACHEXIO: Evaluation of body composition changes and immunotherapy in patients with metastatic cancer.

209 Background: Given body composition predicts toxicity for patients receiving cytotoxic chemotherapy, we explored changes in body composition and biomarkers as predictors of immune-related adverse events (irAEs) and health care utilization. Methods: We conducted a longitudinal study of patients with metastatic solid tumor receiving immunotherapy (07/2014-10/2017). Eligible patients had a computed tomography (CT) scan prior to first-line immunotherapy with at least two additional CT scans at three, six or nine months after immunotherapy initiation. We analyzed body composition using cross-sectional CT scans at the third lumbar vertebra. We utilized mixed effect linear regression models to assess longitudinal changes in body composition (weight, skeletal muscle, total adipose). We examined associations of baseline body composition and biomarkers (albumin, neutrophil-lymphocyte ratio (NLR)) with the incidence of irAEs and healthcare utilization (hospitalizations/ED visits) using logistic regression. Results: Of 140 patients treated with immunotherapy, 61 met inclusion criteria. The majority (80%) received prior chemotherapy and the most common malignancies included lung (26%), head and neck (20%), and melanoma (20%). We found that one-third (n=19) experienced an irAE and colitis (53%) was the most common irAE. Patients experienced substantial weight loss over time (B= -1.88, p&lt;0.001) with a decrease both in skeletal muscle (B= -3.08, p=0.001) and total adipose tissue (B =-50.44, p&lt;0.001). We found greater skeletal muscle at baseline was associated with lower risk of health care utilization (OR 0.98, 95% CI: 0.965-0.998, p=0.03). We observed no association with biomarkers and/or body composition variables with irAEs or health care utilization. Conclusions: Patients with metastatic cancer receiving immunotherapy lose weight including skeletal muscle and adipose tissue. Aside from higher baseline skeletal muscle predicting less health care utilization, we did not observe any other associations between body composition changes and irAEs or health care utilization.

EGCG Reduces Obesity and White Adipose Tissue Gain Partly Through AMPK Activation in Mice

(-)-Epigallocatechin-3-gallate (EGCG), which is the most abundant catechin in green tea, has many potential health benefits, including decreased weight gain and/or adipose tissue weight. Suggested mechanisms for body weight reduction by EGCG include: (1) a decrease in calorie intake and (2) activation of AMPK in liver, skeletal muscle, and white adipose tissue. However, only one study supports the AMPK hypothesis. To determine the role of AMPK in EGCG-induced reduction of body weight, we administrated 50 mg/kg and 100 mg/kg per day to mice, together with a high-fat diet (HFD), for 20 weeks. EGCG had a significant effect on obesity and decrease in epididymal adipose tissue weight, and also affected serum lipid characteristics, including triglyceride, cholesterol (CHOL), and high- and low-density lipoprotein CHOL (HDL-C, LDL-C) concentrations. In addition, EGCG increased the excretion of free fatty acids from feces. By measuring the mRNA expression levels of genes involved in lipid metabolism, we found that EGCG inhibited the expression of genes involved in the synthesis of de novo fatty acids (acc1, fas, scd1, c/ebpβ, pparγ, and srebp1) and increased the expression of genes associated with lipolysis (hsl) and lipid oxidization in white adipose tissue, in both the HFD and the EGCG groups. However, EGCG significantly increased the expression of genes involved in the synthesis of de novo fatty acids compared with the HFD group. Increased AMPK activity was found in both subcutaneous and epididymal adipose tissues. In conclusion, EGCG can decrease obesity and epididymal white adipose tissue weight in mice, only partially via activation of AMPK.

Sarcopenia is a reliable prognostic factor in patients with advanced pancreatic cancer receiving FOLFIRINOX chemotherapy

Background/objectivesFOLFIRINOX is the reliable treatments for pancreatic cancer, but it has a relatively high toxicity and the selection of suitable patients for this regimen remains challenge. On the other hand, sarcopenia is one of the important prognostic factors of pancreatic cancer. The aim of this study was to investigate the effect of sarcopenia on overall survival (OS) and time to treatment failure (TTF) in patients with pancreatic cancer who received FOLFIRINOX. MethodsClinical data of consecutive patients treated with FOLFIRINOX at our institution from 2011 to 2017 was retrospectively reviewed. Skeletal muscle index (SMI) and adipose tissue index (ATI) at the third lumbar spine level was calculated from computed tomography (CT) images. The association between clinical factors (SMI and ATI), and OS and TTF were determined using univariate and multivariate analyses. ResultsWe assessed 82 patients. The median OS of sarcopenia and the non-sarcopenia patients were 11.3 and 17.0 months, respectively (hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.43–4.32; p = 0.001). Median TTF was 3.0 and 6.1 months in the sarcopenia and the non-sarcopenia patients, respectively (HR, 1.67; 95% CI, 1.03–2.71; p = 0.032). Multivariate analyses revealed that sarcopenia (HR, 1.37; 95% CI, 1.01–1.87; p = 0.045) was an independent prognostic factor of OS. High ATI (p = 0.022) and sarcopenic obesity (p = 0.008) were significantly associated with hematologic toxicity. ConclusionsSarcopenia is an independent indicator of poor prognosis in patients with pancreatic cancer who received FOLFIRINOX, while ATI and sarcopenic obesity predicted severe hematologic toxicity.

Impact of Above-Average Proanabolic Nutrients Is Overridden by High Protein and Energy Intake in the Muscle-Tendon Unit Characteristics of Middle- to Older-Aged Adults

BackgroundThe impact, within a single cohort, of independent modulators of skeletal muscle quality, including age, adiposity and obesity, habitual nutritional intake, and physical activity (PA), is unclear. ObjectiveWe examined the bivariate associations between age, adiposity, habitual nutritional intake, and PA against 11 key intrinsic muscle-tendon unit (MTU) characteristics to identify the strongest predictors. We also compared overall profile differences between MTU categories with the use of z scores shown in radar graphs. MethodsFifty untrained independently living men (n = 15) and women (n = 35) aged 43–80 y (mean ± SD: 64 ±9 y) were categorized by adiposity [men: normal adiposity (NA) <28%, high adiposity (HA) ≥28%; women: NA <40%, HA ≥40%] and body mass index [BMI (in kg/m2); normal: 18 to <25; overweight: ≥25 to <30; and obese: ≥30]. Group differences were examined by body composition assessed with the use of dual-energy X-ray absorptiometry, habitual nutritional intake through a 3-d food diary, PA (work, leisure, sport) using the Baecke questionnaire, 14 serum cytokine concentrations using multiplex luminometry, and 11 MTU characteristics of the gastrocnemius medialis using a combination of isokinetic dynamometry, electromyography, and ultrasonography. ResultsInterestingly, classification by BMI highlighted differences between normal and obese individuals in 6 of 11 MTU characteristics (P < 0.001 to P = 0.043). No significant differences were reported in serum cytokine concentrations between adiposity and BMI classifications. BMI predicted 8 of 11 (r = 0.62–0.31, P < 0.001 to P = 0.032), daily energy intake predicted 7 of 11 (r = 0.45–0.34, P = 0.002–0.036), age predicted 5 of 11 (r = −0.49–0.32, P < 0.001 to P = 0.032), work-based PA predicted 5 of 11 (r = 0.43–0.32, P = 0.003–0.048), and adiposity predicted 4 of 11 (r = 0.51–0.33, P < 0.001 to P = 0.022) MTU characteristics. Mathematical z scores and radar graphs showed how endocrine and dietary profiles, but not PA, differed between the top and bottom ∼20% of muscle unit size and specific force. ConclusionsGiven the number of factors associated with MTU, education should be targeted to both adequate food quantity and quality (especially protein intake) and increasing habitual moderate to vigorous PA while decreasing sedentary behavior. Specific endocrine variables are also proposed as key pharmaceutical targets.

Effect of l-arginine on energy metabolism, skeletal muscle and brown adipose tissue in South Asian and Europid prediabetic men: a randomised double-blinded crossover study

Aims/hypothesisIndividuals of South Asian origin are at increased risk of developing type 2 diabetes mellitus and associated comorbidities compared with Europids. Disturbances in energy metabolism may contribute to this increased risk. Skeletal muscle and possibly also brown adipose tissue (BAT) are involved in human energy metabolism and nitric oxide (NO) is suggested to play a pivotal role in regulating mitochondrial biogenesis in both tissues. We aimed to investigate the effects of 6 weeks of supplementation with l-arginine, a precursor of NO, on energy metabolism by BAT and skeletal muscle, as well as glucose metabolism in South Asian men compared with men of European descent.MethodsWe included ten Dutch South Asian men (age 46.5 ± 2.8 years, BMI 30.1 ± 1.1 kg/m2) and ten Dutch men of European descent, that were similar with respect to age and BMI, with prediabetes (fasting plasma glucose level 5.6–6.9 mmol/l or plasma glucose levels 2 h after an OGTT 7.8–11.1 mmol/l). Participants took either l-arginine (9 g/day) or placebo orally for 6 weeks in a randomised double-blind crossover study. Participants were eligible to participate in the study when they were aged between 40 and 55 years, had a BMI between 25 and 35 kg/m2 and did not have type 2 diabetes. Furthermore, ethnicity was defined as having four grandparents of South Asian or white European origin, respectively. Blinding of treatment was done by the pharmacy (Hankintatukku) and an independent researcher from Leiden University Medical Center randomly assigned treatments by providing a coded list. All people involved in the study as well as participants were blinded to group assignment. After each intervention, glucose tolerance was determined by OGTT and basal metabolic rate (BMR) was determined by indirect calorimetry; BAT activity was assessed by cold-induced [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography–computed tomography scanning. In addition, a fasting skeletal muscle biopsy was taken and analysed ex vivo for respiratory capacity using a multisubstrate protocol. The primary study endpoint was the effect of l-arginine on BAT volume and activity.Resultsl-Arginine did not affect BMR, [18F]FDG uptake by BAT or skeletal muscle respiration in either ethnicity. During OGTT, l-arginine lowered plasma glucose concentrations (AUC0–2 h − 9%, p < 0.01), insulin excursion (AUC0–2 h − 26%, p < 0.05) and peak insulin concentrations (−26%, p < 0.05) in Europid but not South Asian men. This coincided with enhanced cold-induced glucose oxidation (+44%, p < 0.05) in Europids only. Of note, in skeletal muscle biopsies several respiration states were consistently lower in South Asian men compared with Europid men.Conclusions/interpretationl-Arginine supplementation does not affect BMR, [18F]FDG uptake by BAT, or skeletal muscle mitochondrial respiration in Europid and South Asian overweight and prediabetic men. However, l-arginine improves glucose tolerance in Europids but not in South Asians. Furthermore, South Asian men have lower skeletal muscle oxidative capacity than men of European descent.FundingThis study was funded by the EU FP7 project DIABAT, the Netherlands Organization for Scientific Research, the Dutch Diabetes Research Foundation and the Dutch Heart Foundation.Trial registration:ClinicalTrials.gov NCT02291458.

Exercise training increases CISD family protein expression in murine skeletal muscle and white adipose tissue

Mitochondrial function in skeletal muscle and white adipose tissue (WAT) declines with aging and the progression of type 2 diabetes and insulin resistance. Although exercise increases mitochondrial biogenesis and function in both tissues, the molecular mechanisms are not fully understood. CDGSH iron sulfur domain-containing proteins (CISDs) are a novel family of proteins that regulate mitochondrial activity and biogenesis. However, the relationship between exercise and CISD expression is unclear. We addressed this in the present study by examining changes in the expression of CISDs and mitochondrial proteins in skeletal muscle and WAT of mice subjected to chronic exercise training. Mice were randomly assigned to either the sedentary or exercise group and were housed for 4 weeks in a standard cage without or with a running wheel, respectively. CISD and mitochondrial protein levels in the plantaris and soleus muscles and epididymal WAT were evaluated by western blotting. Chronic exercise increased CISD1 and CISD2 as well as mitochondrial protein expression in plantaris muscle and WAT but not soleus muscle. Moreover, this exercise-induced adaptation was strongly correlated with mitochondrial protein expression. Thus, mitochondrial biogenesis induced by chronic exercise coincides with the expression of CISDs in specific tissues, which may be critical for the maintenance of mitochondrial integrity.

Female Mice Have Higher Angiogenesis in Perigonadal Adipose Tissue Than Males in Response to High-Fat Diet.

Background: Impaired capillary growth (angiogenesis) in skeletal muscle and adipose tissue contributes to the development of metabolic disorders in obese males. This association remains unexplored in females, despite mounting evidence that endothelial cells have sex-specific transcriptional profiles. Therefore, herein we assessed whether males and females show distinct angiogenic capacities in response to diet-induced obesity.Methods: Age-matched male and female mice were fed normal chow or high-fat obesogenic diets for 16 weeks. At the end of diet period, systemic glucose disposal was assessed as well as insulin sensitivity of skeletal muscle and visceral adipose tissue. Capillary content and the expression of angiogenic regulators were also evaluated in these tissues.Results: When placed on a high-fat diet, female mice gained less weight than males and showed a metabolic phenotype similar to NC-fed mice, contrasting with the impaired whole-body glucose metabolism observed in high-fat-fed males. However, high-fat-feeding elevated serum lipid levels similarly in male and female mice. Although skeletal muscle of high-fat–fed female mice had higher insulin sensitivity than male counterparts, no sex difference was detected in muscle capillarization. Metabolic functions of perigonadal white adipose tissue (pgWAT) were retained in high-fat-fed females, as evidenced by smaller adipocytes with preserved insulin sensitivity, greater responsiveness to isoproterenol, higher expression of Adiponectin and a lower ratio of Leptin:Adiponectin mRNA. An enhanced browning phenotype was detected in HF-fed female adipocytes with upregulation of Ucp1 expression. PgWAT from high-fat-fed females also showed augmented capillary number and expression of endothelial cell markers, which was associated with elevated mRNA levels of pro-angiogenic mediators, including vascular endothelial growth factor A (Vegfa) and its receptor (Vegfr2), the Notch ligand Jagged-1 (Jag1) and Angiopoietin-2 (Angpt2).Conclusion: Taken together, our findings provide novel evidence that visceral adipose tissue of female mice display greater levels of pro-angiogenic factors and vascularity than males in response to high-fat diet. This phenotype is associated with preserved metabolic homeostasis at both tissue and systemic levels. Our study discloses that a thus-far-unappreciated sex-specific difference in the regulation of adipose angiogenesis may contribute to an individual’s susceptibility to developing adipose dysfunction and obesity-related metabolic disturbances.