Social media for obesity education: a general overview for the novice creator.

Rates of obesity continue to rise in the United States and across the globe. Obesity is a risk factor for developing insulin resistance, type 2 diabetes, and cardiovascular disease. For clinicians, other health care providers, and educators, providing patients with accurate and meaningful information about obesity, including lifestyle (diet and exercise) interventions and symptom monitoring, is challenging because of infrequent contact, methods of communication, a lack of effective patient education resources, and inefficient patient feedback methods. Evidence suggests that significantly more patients are now getting their health care information online from general medical websites, disease-specific network communities, and social media. Thus, harnessing the power of technologies, including personal computers and smartphones, with attention to social media may equip health care providers with methods to serve their patients better by addressing challenges, improving indirect patient contact, and enhancing health outcomes. This article aims to provide an overview of technology with a focus on social media use in obesity education and outreach. Practical information is provided related to creating content, delivering content, and managing the social media space for the novice creator.NEW & NOTEWORTHY Rates of obesity continue to increase. Health care providers have a limited time to cover the nuances of obesity. Technology and social media are tools that can help health care workers provide obesity education to a large audience. This article provides the foundations for obesity education content generation and delivery for the novice creator.

Moderate exercise training decreases inflammation in transgenic sickle cell mice.

Chronic systemic inflammation is a pathophysiological feature of sickle cell disease (SCD). Considering that regular exercise exerts multiple beneficial health effects including anti-inflammatory actions, we investigated whether a treadmill training program could minimize the inflammatory state in transgenic sickle cell (SS) mice. To test this hypothesis, SS mice were subjected to a treadmill training protocol of 1h/day, 5days a week for 8weeks. Exercise training increased the percent of venous oxyhemoglobin and sharply decreased the percent of carboxyhemoglobin suggesting that exercise training may limit the proportion of erythrocytes that were deoxygenated in the venous circulation. Exercise training attenuated systemic inflammation as attested by a significant drop in white blood cell (WBC) count and plasma Th1/Th2 cytokine ratio. There was reduction in interleukin-1ß and endothelin-1 mRNA expression in trained sickle mice. The spleen/body mass ratio was significantly decreased in trained sickle mice and there was a strong correlation between the magnitude of congestion and the relative spleen mass in all animals (trained and untrained). We conclude that moderate intensity exercise training, without any noticeable complications, may be associated with limited baseline blood deoxygenation and inflammation in sickle cell mice, and reduce sequestration of sickle erythrocytes/congestion in the spleen.

SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF) is an increasingly recognized clinical complication of metabolic syndrome. No adequate animal model of PH-HFpEF is available, and no effective therapies have been identified to date. A recent study suggested that dietary nitrate improves insulin resistance in endothelial nitric oxide synthase null mice, and multiple studies have reported that both nitrate and its active metabolite, nitrite, have therapeutic activity in preclinical models of pulmonary hypertension. METHODS AND RESULTS: To evaluate the efficacy and mechanism of nitrite in metabolic syndrome associated with PH-HFpEF, we developed a 2-hit PH-HFpEF model in rats with multiple features of metabolic syndrome attributable to double-leptin receptor defect (obese ZSF1) with the combined treatment of vascular endothelial growth factor receptor blocker SU5416. Chronic oral nitrite treatment improved hyperglycemia in obese ZSF1 rats by a process that requires skeletal muscle SIRT3-AMPK-GLUT4 signaling. The glucose-lowering effect of nitrite was abolished in SIRT3-deficient human skeletal muscle cells, and in SIRT3 knockout mice fed a high-fat diet, as well. Skeletal muscle biopsies from humans with metabolic syndrome after 12 weeks of oral sodium nitrite and nitrate treatment (IND#115926) displayed increased activation of SIRT3 and AMP-activated protein kinase. Finally, early treatments with nitrite and metformin at the time of SU5416 injection reduced pulmonary pressures and vascular remodeling in the PH-HFpEF model with robust activation of skeletal muscle SIRT3 and AMP-activated protein kinase. CONCLUSIONS: These studies validate a rodent model of metabolic syndrome and PH-HFpEF, suggesting a potential role of nitrite and metformin as a preventative treatment for this disease.

Adipose triglyceride lipase deletion from adipocytes, but not skeletal myocytes, impairs acute exercise performance in mice.

Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme mediating triacylglycerol hydrolysis in virtually all cells, including adipocytes and skeletal myocytes, and hence, plays a critical role in mobilizing fatty acids. Global ATGL deficiency promotes skeletal myopathy and exercise intolerance in mice and humans, and yet the tissue-specific contributions to these phenotypes remain unknown. The goal of this study was to determine the relative contribution of ATGL-mediated triacylglycerol hydrolysis in adipocytes vs. skeletal myocytes to acute exercise performance. To achieve this goal, we generated murine models with adipocyte- and skeletal myocyte-specific targeted deletion of ATGL. We then subjected untrained mice to acute peak and submaximal exercise interventions and assessed exercise performance and energy substrate metabolism. Impaired ATGL-mediated lipolysis within adipocytes reduced peak and submaximal exercise performance, reduced peripheral energy substrate availability, shifted energy substrate preference toward carbohydrate oxidation, and decreased HSL Ser(660) phosphorylation and mitochondrial respiration within skeletal muscle. In contrast, impaired ATGL-mediated lipolysis within skeletal myocytes was not sufficient to reduce peak and submaximal exercise performance or peripheral energy substrate availability and instead tended to enhance metabolic flexibility during peak exercise. Furthermore, the expanded intramyocellular triacylglycerol pool in these mice was reduced following exercise in association with preserved HSL phosphorylation, suggesting that HSL may compensate for impaired ATGL action in skeletal muscle during exercise. These data suggest that adipocyte rather than skeletal myocyte ATGL-mediated lipolysis plays a greater role during acute exercise in part because of compensatory mechanisms that maintain lipolysis in muscle, but not adipose tissue, when ATGL is absent.

A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle.

AIMS/HYPOTHESIS: Insulin-sensitive tissues (muscle, liver) of individuals with obesity and type 2 diabetes mellitus are in a state of low-grade inflammation, characterised by increased Toll-like receptor (TLR) expression and TLR-driven signalling. However, the cause of this mild inflammatory state is unclear. We tested the hypothesis that a prolonged mild increase in plasma NEFA will increase TLR expression and TLR-driven signalling (nuclear factor κB [NFκB] and mitogen-activated kinase [MAPK]) and impair insulin action in muscle of lean healthy individuals. METHODS: Twelve lean, normal-glucose-tolerant participants were randomised to receive a 48 h infusion (30 ml/h) of saline or Intralipid followed by a euglycaemic-hyperinsulinaemic clamp. Vastus lateralis muscle biopsies were performed before and during the clamp. RESULTS: Lipid infusion impaired insulin-stimulated IRS-1 tyrosine phosphorylation and reduced peripheral insulin sensitivity (p < 0.01). The elevation in circulating NEFA increased expression of TLR3, TLR4 and TLR5, and several MAPK (MAPK8, MAP4K4, MAP2K3) and inhibitor of κB kinase-NFκB (CHUK [IKKA], c-REL [REL] and p65 [RELA, NFKB3, p65]) signalling genes (p < 0.05). The lipid infusion also increased extracellular signal-regulated kinase (ERK) phosphorylation (p < 0.05) and tended to reduce the content of inhibitor of kappa Bα (p = 0.09). The muscle content of most diacylglycerol, ceramide and acylcarnitine species was unaffected. In summary, insulin resistance induced by prolonged low-dose lipid infusion occurs together with increased TLR-driven inflammatory signalling and impaired insulin-stimulated IRS-1 tyrosine phosphorylation. CONCLUSIONS/INTERPRETATION: A sustained, mild elevation in plasma NEFA is sufficient to increase TLR expression and TLR-driven signalling (NFκB and MAPK) in lean individuals. The activation of this pathway by NEFA may be involved in the pathogenesis of insulin resistance in humans. TRIAL REGISTRATION: ClinicalTrials.gov NCT01740817.

Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance.

We hypothesized that acute lipid-induced insulin resistance would be attenuated in high-oxidative muscle of lean trained (LT) endurance athletes due to their enhanced metabolic flexibility and mitochondrial capacity. Lean sedentary (LS), obese sedentary (OS), and LT participants completed two hyperinsulinemic euglycemic clamp studies with and without (glycerol control) the coinfusion of Intralipid. Metabolic flexibility was measured by indirect calorimetry as the oxidation of fatty acids and glucose during fasted and insulin-stimulated conditions, the latter with and without lipid oversupply. Muscle biopsies were obtained for mitochondrial and insulin-signaling studies. During hyperinsulinemia without lipid, glucose infusion rate (GIR) was lowest in OS due to lower rates of nonoxidative glucose disposal (NOGD), whereas state 4 respiration was increased in all groups. Lipid infusion reduced GIR similarly in all subjects and reduced state 4 respiration. However, in LT subjects, fat oxidation was higher with lipid oversupply, and although glucose oxidation was reduced, NOGD was better preserved compared with LS and OS subjects. Mitochondrial performance was positively associated with better NOGD and insulin sensitivity in both conditions. We conclude that enhanced mitochondrial performance with exercise is related to better metabolic flexibility and insulin sensitivity in response to lipid overload.

Effect of a sustained reduction in plasma free fatty acid concentration on insulin signalling and inflammation in skeletal muscle from human subjects.

Free fatty acids (FFAs) have been implicated in the pathogenesis of insulin resistance. Reducing plasma FFA concentration in obese and type 2 diabetic (T2DM) subjects improves insulin sensitivity. However, the molecular mechanism by which FFA reduction improves insulin sensitivity in human subjects is not fully understood. In the present study, we tested the hypothesis that pharmacological FFA reduction enhances insulin action by reducing local (muscle) inflammation, leading to improved insulin signalling. Insulin-stimulated total glucose disposal (TGD), plasma FFA species, muscle insulin signalling, IBα protein, c-Jun phosphorylation, inflammatory gene (toll-like receptor 4 and monocyte chemotactic protein 1) expression, and ceramide and diacylglycerol (DAG) content were measured in muscle from a group of obese and T2DM subjects before and after administration of the antilipolytic drug acipimox for 7 days, and the results were compared to lean individuals. We found that obese and T2DM subjects had elevated saturated and unsaturated FFAs in plasma, and acipimox reduced all FFA species. Acipimox-induced reductions in plasma FFAs improved TGD and insulin signalling in obese and T2DM subjects. Acipimox increased IBα protein (an indication of decreased IB kinase-nuclear factor B signalling) in both obese and T2DM subjects, but did not affect c-Jun phosphorylation in any group. Acipimox also decreased inflammatory gene expression, although this reduction only occurred in T2DM subjects. Ceramide and DAG content did not change. To summarize, pharmacological FFA reduction improves insulin signalling in muscle from insulin-resistant subjects. This beneficial effect on insulin action could be related to a decrease in local inflammation. Notably, the improvements in insulin action were more pronounced in T2DM, indicating that these subjects are more susceptible to the toxic effect of FFAs.

Lower mitochondrial respiration does not lead to decreased fat oxidation in young African American women without obesity.

OBJECTIVE: The prevalence of type 2 diabetes in African American women (AAW) is nearly twice that of White women. Lower insulin sensitivity and decreased mitochondrial function may be contributing factors. The purpose of this study was to compare fat oxidation in AAW and White women. METHODS: Participants were 22 AAW and 22 White women, matched for age (18.7-38.3 years) and BMI (< 28 kg/m2). Participants completed two submaximal (50% VO2max) exercise tests with indirect calorimetry and stable isotope tracers to assess total, plasma, and intramyocellular triglyceride fat oxidation. RESULTS: The respiratory quotient during the exercise test was nearly identical in AAW and White women (0.813 ± 0.008 vs. 0.810 ± 0.008, p = 0.83). Although absolute total and plasma fat oxidation was lower in AAW, adjusting for the lower workload in AAW eliminated these racial differences. There was no racial difference in plasma and intramyocellular triglyceride source of fat for oxidation. No racial differences were observed in rates of ex vivo fat oxidation. Exercise efficiency was lower in AAW when adjusted to leg fat free mass. CONCLUSIONS: The data suggest that fat oxidation is not lower in AAW compared with White women, but additional studies are needed across exercise intensity, body weight, and age to confirm these results.

Medical student coping and performance in simulated disasters.

OBJECTIVES: Coping with the stress of real and simulated disasters is thought to be integral to the performance of emergency medicine providers. Yet, little is known about which coping strategies are employed in these scenarios and whether differential use of strategies predicts actual clinical and interpersonal performance. METHODS: Thirty-four medical students were evaluated by trained simulated patients and physician observers across 111 clinical encounters during a simulated disaster. Linear Mixed Effects Modelling was used to test study hypotheses while accounting for demographic variables, psychological factors, and the dependency of multiple encounters for each participant. RESULTS: Results indicated that multilevel modeling was necessary. Positive thinking positively predicted observed clinical performance whereas avoidant coping was a negative predictor. Anticipatory anxiety and positive affect, but not reported coping, positively predicted student interpersonal performance. CONCLUSIONS: The present study indicates that the way medical students report managing the stress of disaster scenarios has clear links to their observed clinical performance above and beyond demographic and psychological factors. It further demonstrates the feasibility of empirically identifying specific coping strategies that may be important targets for disaster response training.

Decreased Mitochondrial Dynamics Is Associated with Insulin Resistance, Metabolic Rate, and Fitness in African Americans.

CONTEXT: African American women (AAW) have a higher incidence of insulin resistance and are at a greater risk for the development of obesity and type 2 diabetes than Caucasian women (CW). Although several factors have been proposed to mediate these racial disparities, the mechanisms remain poorly defined. We previously demonstrated that sedentary lean AAW have lower peripheral insulin sensitivity, reduced maximal aerobic fitness (VO2max), and lower resting metabolic rate (RMR) than CW. We have also demonstrated that skeletal muscle mitochondrial respiration is lower in AAW and appears to play a role in these racial differences. OBJECTIVE: The goal of this study was to assess mitochondrial pathways and dynamics to examine the potential mechanisms of lower insulin sensitivity, RMR, VO2max, and mitochondrial capacity in AAW. DESIGN: To achieve this goal, we assessed several mitochondrial pathways in skeletal muscle using gene array technology and semiquantitative protein analysis. RESULTS: We report alterations in mitochondrial pathways associated with inner membrane small molecule transport genes, fusion-fission, and autophagy in lean AAW. These differences were associated with lower insulin sensitivity, RMR, and VO2max. CONCLUSIONS: Together these data suggest that the metabolic racial disparity of insulin resistance, RMR, VO2max, and mitochondrial capacity may be mediated by perturbations in mitochondrial pathways associated with membrane transport, fission-fusion, and autophagy. The mechanisms contributing to these differences remain unknown.

WASH Regulates Glucose Homeostasis by Facilitating Glut2 Receptor Recycling in Pancreatic ß-Cells.

WASH is an endosomal protein belonging to the Wiskott-Aldrich syndrome protein superfamily that participates in endosomal receptor trafficking by facilitating tubule fission via activation of the ubiquitously expressed Arp2/3 complex. While several studies have begun to elucidate an understanding of the functions of WASH in cells lines, the in vivo function of WASH has not been fully elucidated, since total body deletion in mice leads to early embryonic lethality. To circumvent this problem, we have used a WASH conditional knockout mouse model to investigate the role of WASH in the pancreas. We find that pancreas-specific deletion of WASH leads to impaired blood glucose clearance and reduced insulin release upon glucose stimulation. Furthermore, WASH depletion results in impaired trafficking of Glut2 in pancreatic ß-cells as a consequence of an intracellular accumulation of Glut2 and overall decreased levels of Glut2 protein. Taken together, these results indicate that WASH participates in pancreatic ß-cell glucose sensing and whole-body glucose homeostasis. Thus, patients harboring mutations in components of the WASH complex could be at risk for developing type 2 diabetes.

Effects of Individualized Treadmill Endurance Training on Oxidative Stress in Skeletal Muscles of Transgenic Sickle Mice.

Oxidative stress is a key feature in the pathophysiology of sickle cell disease. Endurance training has been shown to reduce oxidative stress in the heart and the liver of sickle mice. However, the effects of endurance training on skeletal muscles, which are major producers of reactive oxygen species during exercise, are currently unknown. The aim of this study was to evaluate the effect of sickle genotype on prooxidant/antioxidant response to individualized endurance training in skeletal muscles of sickle mice. Healthy and homozygous Townes sickle mice were divided into trained or sedentary groups. Maximal aerobic speed and V̇O2 peak were determined using an incremental test on a treadmill. Trained mice ran at 40% to 60% of maximal aerobic speed, 1 h/day, 5 days/week for 8 weeks. Oxidative stress markers, prooxidant/antioxidant response, and citrate synthase enzyme activities were assessed in the gastrocnemius, in the plantaris, and in the soleus muscles. Maximal aerobic speed and V̇O2 peak were significantly reduced in sickle compared to healthy mice (-57% and -17%; p < 0.001). NADPH oxidase, superoxide dismutase, and catalase activities significantly increased after training in the gastrocnemius of sickle mice only. A similar trend was observed for citrate synthase activity in sickle mice (p = 0.06). In this study, we showed an adaptive response to individualized endurance training on the prooxidant/antioxidant balance in the gastrocnemius, but neither in the plantaris nor in the soleus of trained sickle mice, suggesting an effect of sickle genotype on skeletal muscle response to endurance treadmill training.

Glycogen Synthase Kinase-3 Inhibition Sensitizes Pancreatic Cancer Cells to Chemotherapy by Abrogating the TopBP1/ATR-Mediated DNA Damage Response.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a predominantly fatal common malignancy with inadequate treatment options. Glycogen synthase kinase 3ß (GSK-3ß) is an emerging target in human malignancies including PDAC.Experimental Design: Pancreatic cancer cell lines and patient-derived xenografts were treated with a novel GSK-3 inhibitor 9-ING-41 alone or in combination with chemotherapy. Activation of the DNA damage response pathway and S-phase arrest induced by gemcitabine were assessed in pancreatic tumor cells with pharmacologic inhibition or siRNA depletion of GSK-3 kinases by immunoblotting, flow cytometry, and immunofluorescence. RESULTS: 9-ING-41 treatment significantly increased pancreatic tumor cell killing when combined with chemotherapy. Inhibition of GSK-3 by 9-ING-41 prevented gemcitabine-induced S-phase arrest suggesting an impact on the ATR-mediated DNA damage response. Both 9-ING-41 and siRNA depletion of GSK-3 kinases impaired the activation of ATR leading to the phosphorylation and activation of Chk1. Mechanistically, depletion or knockdown of GSK-3 kinases resulted in the degradation of the ATR-interacting protein TopBP1, thus limiting the activation of ATR in response to single-strand DNA damage. CONCLUSIONS: These data identify a previously unknown role for GSK-3 kinases in the regulation of the TopBP1/ATR/Chk1 DNA damage response pathway. The data also support the inclusion of patients with PDAC in clinical studies of 9-ING-41 alone and in combination with gemcitabine.

Separate and combined effects of exercise training and weight loss on exercise efficiency and substrate oxidation.

Perturbations in body weight have been shown to affect energy expenditure and efficiency during physical activity. The separate effects of weight loss and exercise training on exercise efficiency or the proportion of energy derived from fat oxidation during physical activity, however, are not known. The purpose of this study was to determine the separate and combined effects of exercise training and weight loss on metabolic efficiency, economy (EC), and fat oxidation during steady-state moderate submaximal exercise. Sixty-four sedentary older (67 +/- 0.5 yr) overweight to obese (30.7 +/- 0.4 kg/m(2)) volunteers completed 4 mo of either diet-induced weight loss (WL; n = 11), exercise training (EX; n = 36), or the combination of both interventions (WLEX; n = 17). Energy expenditure, gross efficiency (GE), EC, and proportion of energy expended from fat (EF) were determined during a 1-h submaximal (50% of peak aerobic capacity) cycle ergometry exercise before the intervention and at the same absolute work rate after the intervention. We found that EX increased GE by 4.7 +/- 2.2%. EC was similarly increased by 4.2 +/- 2.1% by EX. The addition of concomitant WL to EX (WLEX) resulted in greater increases in GE (9.0 +/- 3.3%) compared with WL alone but not compared with EX alone. These effects remained after adjusting for changes in lean body mass. The proportion of energy derived from fat during the bout of moderate exercise increased with EX and WLEX but not with WL. From these findings, we conclude that exercise training, either alone or in combination with weight loss, increases both exercise efficiency and the utilization of fat during moderate physical activity in previously sedentary, obese older adults. Weight loss alone, however, significantly improves neither efficiency nor utilization of fat during exercise.

Mitochondrial Respiration is Associated with Lower Energy Expenditure and Lower Aerobic Capacity in African American Women.

OBJECTIVE: Reasons for the higher obesity prevalence in African American women (AAW) compared with Caucasian women (CW) are unknown. Energy expenditure and maximal aerobic capacity (VO2 max) are lower in AAW. It was hypothesized that these differences are explained by skeletal muscle characteristics, particularly mitochondrial content and function. METHODS: Multivariate regression analyses were used to examine the relationships between energy expenditure (resting and during a hyperinsulinemic-euglycemic clamp) and VO2 max versus body composition, physical activity, and skeletal muscle mitochondrial measurements in AAW and CW. RESULTS: In AAW, VO2 max was lower (P < 0.0001). Body-composition-adjusted energy expenditure during the clamp was lower in AAW (P < 0.002). Physical activity was similar in both groups. After adjusting for mitochondrial respiration, racial differences in energy expenditure and VO2 max were no longer present. Another novel finding was that a thermogenic response to the clamp was observed in CW (+53 ± 22 kcal/d; P < 0.03) but not in AAW (-19 ± 24 kcal/d; P = 0.43). CONCLUSIONS: AAW and CW show differences in adjusted energy expenditure and aerobic capacity that are largely accounted for by differences in skeletal muscle mitochondrial oxidative characteristics. Further research is needed to determine whether lower mitochondrial respiration and lower thermogenesis are risk factors for obesity in AAW.

Effect of acute physiological free fatty acid elevation in the context of hyperinsulinemia on fiber type-specific IMCL accumulation.

It is well described that increasing free fatty acids (FFAs) to high physiological levels reduces insulin sensitivity. In sedentary humans, intramyocellular lipid (IMCL) is inversely related to insulin sensitivity. Since muscle fiber composition affects muscle metabolism, whether FFAs induce IMCL accumulation in a fiber type-specific manner remains unknown. We hypothesized that in the setting of acute FFA elevation by lipid infusion within the context of a hyperinsulinemic-euglycemic clamp, IMCL will preferentially accumulate in type 1 fibers. Normal-weight participants (n = 57, mean ± SE: age 24 ± 0.6 yr, BMI 22.2 ± 0.3 kg/m2) who were either endurance trained or sedentary by self-report were recruited from the University of Minnesota (n = 31, n = 15 trained) and University of Pittsburgh (n = 26, n = 14 trained). All participants underwent a hyperinsulinemic-euglycemic clamp in the context of a 6-h infusion of either lipid or glycerol control. A vastus lateralis muscle biopsy was obtained at baseline and end-infusion (6 h). The muscle biopsies were processed and analyzed at the University of Pittsburgh for fiber type-specific IMCL accumulation by Oil-Red-O staining. Regardless of training status, acute elevation of FFAs to high physiological levels (~400-600 meq/l) increased IMCL preferentially in type 1 fibers (+35 ± 11% compared with baseline, +29 ± 11% compared with glycerol control: P < 0.05). The increase in IMCL correlated with a decline in insulin sensitivity as measured by the hyperinsulinemic-euglycemic clamp (r = -0.32, P < 0.01) independent of training status. Regardless of training status, increase of FFAs to a physiological range within the context of hyperinsulinemia shows preferential IMCL accumulation in type 1 fibers.NEW & NOTEWORTHY This novel human study examined the effects of FFA elevation in the setting of hyperinsulinemia on accumulation of fat in specific types of muscle fibers. Within the context of the hyperinsulinemic-euglycemic clamp, we found that an increase of FFAs to a physiological range sufficient to reduce insulin sensitivity is associated with preferential IMCL accumulation in type 1 fibers.

Calorie Restriction-induced Weight Loss and Exercise Have Differential Effects on Skeletal Muscle Mitochondria Despite Similar Effects on Insulin Sensitivity.

BACKGROUND: Skeletal muscle insulin resistance and reduced mitochondrial capacity have both been reported to be affected by aging. The purpose of this study was to compare the effects of calorie restriction-induced weight loss and exercise on insulin resistance, skeletal muscle mitochondrial content, and mitochondrial enzyme activities in older overweight to obese individuals. METHODS: Insulin-stimulated rates of glucose disposal (Rd) were determined using the hyperinsulinemic euglycemic clamp before and after completing 16 weeks of either calorie restriction to induce weight loss (N = 7) or moderate exercise (N = 10). Mitochondrial volume density, mitochondria membrane content (cardiolipin), and activities of electron transport chain (rotenone-sensitive NADH-oxidase), tricarboxylic acid (TCA) cycle (citrate synthase) and ß-oxidation pathway (ß-hydroxyacyl CoA dehydrogenase; ß-HAD) were measured in percutaneous biopsies of the vastus lateralis before and after the interventions. RESULTS: Rd improved similarly (18.2% ± 9.0%, p < .04) with both weight loss and exercise. Moderate exercise significantly increased mitochondrial volume density (14.5% ± 2.0%, p < .05), cardiolipin content (22.5% ± 13.4%, p < .05), rotenone-sensitive NADH-oxidase (65.7% ± 13.2%, p = .02) and ß-HAD (30.7% ± 6.8%, p ≤ .03) activity, but not citrate synthase activity (10.1% ± 4.0%). In contrast, calorie restriction-induced weight loss did not affect mitochondrial content, NADH-oxidase or ß-HAD, yet increased citrate synthase activity (44.1% ± 21.1%, p ≤ .04). Exercise (increase) or weight loss (decrease) induced a remodeling of cardiolipin with a small (2%-3%), but significant change in the relative content of tetralinoleoyl cardiolipin. CONCLUSION: Exercise increases both mitochondria content and mitochondrial electron transport chain and fatty acid oxidation enzyme activities within skeletal muscle, while calorie restriction-induced weight loss did not, despite similar improvements in insulin sensitivity in overweight older adults.

Chronological Age Does not Influence Ex-vivo Mitochondrial Respiration and Quality Control in Skeletal Muscle.

BACKGROUND: Considerable debate continues to surround the concept of mitochondrial dysfunction in aging muscle. We tested the overall hypothesis that age per se does not influence mitochondrial function and markers of mitochondria quality control, that is, expression of fusion, fission, and autophagy proteins. We also investigated the influence of cardiorespiratory fitness (VO2max) and adiposity (body mass index) on these associations. METHODS: Percutaneous biopsies of the vastus lateralis were obtained from sedentary young (n = 14, 24±3 years), middle-aged (n = 24, 41±9 years) and older adults (n = 20, 78±5 years). A physically active group of young adults (n = 10, 27±5 years) was studied as a control. Mitochondrial respiration was determined in saponin permeabilized fiber bundles. Fusion, fission and autophagy protein expression was determined by Western blot. Cardiorespiratory fitness was determined by a graded exercise test. RESULTS: Mitochondrial respiratory capacity and expression of fusion (OPA1 and MFN2) and fission (FIS1) proteins were not different among sedentary groups despite a wide age range (21 to 88 years). Mitochondrial respiratory capacity and fusion and fission proteins were, however, negatively associated with body mass index, and mitochondrial respiratory capacity was positively associated with cardiorespiratory fitness. The young active group had higher respiration, complex I and II respiratory control ratios, and expression of fusion and fission proteins. Finally, the expression of fusion, fission, and autophagy proteins were linked with mitochondrial respiration. CONCLUSIONS: Mitochondrial respiration and markers of mitochondrial dynamics (fusion and fission) are not associated with chronological age per se, but rather are more strongly associated with body mass index and cardiorespiratory fitness.

Muscle Characteristics and Substrate Energetics in Lifelong Endurance Athletes.

PURPOSE: The goal of this study was to explore the effect of lifelong aerobic exercise (i.e., chronic training) on skeletal muscle substrate stores (intramyocellular triglyceride [IMTG] and glycogen), skeletal muscle phenotypes, and oxidative capacity (ox), in older endurance-trained master athletes (OA) compared with noncompetitive recreational younger (YA) athletes matched by frequency and mode of training. METHODS: Thirteen OA (64.8 ± 4.9 yr) exercising 5 times per week or more were compared with 14 YA (27.8 ± 4.9 yr) males and females. IMTG, glycogen, fiber types, succinate dehydrogenase, and capillarization were measured by immunohistochemistry in vastus lateralis biopsies. Fat-ox and carbohydrate (CHO)-ox were measured by indirect calorimetry before and after an insulin clamp and during a cycle ergometer graded maximal test. RESULTS: V˙O2peak was lower in OA than YA. The OA had greater IMTG in all fiber types and lower glycogen stores than YA. This was reflected in greater proportion of type I and less type II fibers in OA. Type I fibers were similar in size, whereas type II fibers were smaller in OA compared with YA. Both groups had similar succinate dehydrogenase content. Numbers of capillaries per fiber were reduced in OA but with a higher number of capillaries per area. Metabolic flexibility and insulin sensitivity were similar in both groups. Exercise metabolic efficiency was higher in OA. At moderate exercise intensities, carbohydrate-ox was lower in OA but with similar Fat-ox. CONCLUSIONS: Lifelong exercise is associated with higher IMTG content in all muscle fibers and higher metabolic efficiency during exercise that are not explained by differences in muscle fibers types and other muscle characteristics when comparing older with younger athletes matched by exercise mode and frequency.

Resting and exercise energy metabolism in weight-reduced adults with severe obesity.

OBJECTIVE: To determine effects of physical activity (PA) with diet-induced weight loss on energy metabolism in adults with severe obesity. METHODS: Adults with severe obesity (n = 11) were studied across 6 months of intervention, then compared with controls with less severe obesity (n = 7) or normal weight (n = 9). Indirect calorimetry measured energy metabolism during exercise and rest. Markers of muscle oxidation were determined by immunohistochemistry. Data were presented as medians. RESULTS: The intervention induced 7% weight loss (P = 0.001) and increased vigorous PA by 24 min/wk (P = 0.02). During exercise, energy expenditure decreased, efficiency increased (P ≤ 0.03), and fatty acid oxidation (FAO) did not change. Succinate dehydrogenase increased (P = 0.001), but fiber type remained the same. Post-intervention subjects' resting metabolism remained similar to controls. Efficiency was lower in post-intervention subjects compared with normal-weight controls exercising at 25 W (P ≤ 0.002) and compared with all controls exercising at 60% VO2peak (P ≤ 0.019). Resting and exercise FAO of post-intervention subjects remained similar to adults with less severe obesity. Succinate dehydrogenase and fiber type were similar across all body weight statuses. CONCLUSIONS: While metabolic adaptations to PA during weight loss occur in adults with severe obesity, FAO does not change. Resulting FAO during rest and exercise remains similar to adults with less severe obesity.