Transcriptional programming of translation by BCL6 controls skeletal muscle proteostasis.

Skeletal muscle is dynamically controlled by the balance of protein synthesis and degradation. Here we discover an unexpected function for the transcriptional repressor B cell lymphoma 6 (BCL6) in muscle proteostasis and strength in mice. Skeletal muscle-specific Bcl6 ablation in utero or in adult mice results in over 30% decreased muscle mass and force production due to reduced protein synthesis and increased autophagy, while it promotes a shift to a slower myosin heavy chain fibre profile. Ribosome profiling reveals reduced overall translation efficiency in Bcl6-ablated muscles. Mechanistically, tandem chromatin immunoprecipitation, transcriptomic and translational analyses identify direct BCL6 repression of eukaryotic translation initiation factor 4E-binding protein 1 (Eif4ebp1) and activation of insulin-like growth factor 1 (Igf1) and androgen receptor (Ar). Together, these results uncover a bifunctional role for BCL6 in the transcriptional and translational control of muscle proteostasis.

Teleosts as behaviour test models for social stress.

Stress is an important aspect of our everyday life and exposure to it is an unavoidable occurrence. In humans, this can come in the form of social stress or physical stress from an injury. Studies in animal models have helped researchers to understand the body's adaptive response to stress in human. Notably, the use of behavioural tests in animal models plays a pivotal role in understanding the neural, endocrine and behavioural changes induced by social stress. Under socially stressed conditions, behavioural parameters are often measured physiological and molecular parameters as changes in behaviour are direct responses to stress and are easily assessed by behavioural tests. Throughout the past few decades, the rodent model has been used as a well-established animal model for stress and behavioural changes. Recently, more attention has been drawn towards using fish as an animal model. Common fish models such as zebrafish, medaka, and African cichlids have the advantage of a higher rate of reproduction, easier handling techniques, sociability and most importantly, share evolutionary conserved genetic make-up, neural circuitry, neuropeptide molecular structure and function with mammalian species. In fact, some fish species exhibit a clear diurnal or seasonal rhythmicity in their stress response, similar to humans, as opposed to rodents. Various social stress models have been established in fish including but not limited to chronic social defeat stress, social stress avoidance, and social stress-related decision-making. The huge variety of behavioural patterns in teleost also aids in the study of more behavioural phenotypes than the mammalian species. In this review, we focus on the use of fish models as alternative models to study the effects of stress on different types of behaviours. Finally, fish behavioural tests against the typical mammalian model-based behavioural test are compared and discussed for their viability.

Nanoparticles from Microalgae and Their Biomedical Applications.

Over the years, microalgae have been a source of useful compounds mainly used as food and dietary supplements. Recently, microalgae have been used as a source of metabolites that can participate in the synthesis of several nanoparticles through inexpensive and environmentally friendly routes alternative to chemical synthesis. Notably, the occurrence of global health threats focused attention on the microalgae application in the medicinal field. In this review, we report the influence of secondary metabolites from marine and freshwater microalgae and cyanobacteria on the synthesis of nanoparticles that were applied as therapeutics. In addition, the use of isolated compounds on the surface of nanoparticles to combat diseases has also been addressed. Although studies have proven the beneficial effect of high-value bioproducts on microalgae and their potential in medicine, there is still room for understanding their exact role in the human body and translating lab-based research into clinical trials.

Relationship between muscle venous blood oxygenation and near-infrared spectroscopy: quantitative analysis of the Hb and Mb contributions.

A linear relationship between skeletal muscle venous ([Formula: see text]) and oxygenated (ΔHbMbO2,N) or deoxygenated (ΔHHbMbN) near-infrared spectroscopy (NIRS) signals suggest a main hemoglobin (Hb) contribution to the NIRS signal. However, experimental, and computational evidence supports a significant contribution of myoglobin (Mb) to the NIRS. Venous and NIRS measurements from a canine model of muscle oxidative metabolism (Sun Y, Ferguson BS, Rogatzki MJ, McDonald JR, Gladden LB. Med Sci Sports Exerc 48(10):2013-2020, 2016) were integrated into a computational model of muscle O2 transport and utilization to evaluate whether the relationship between venous and NIRS oxygenation can be affected by a significant Mb contribution to the NIRS signals. The mathematical model predicted well the measure of the changes of [Formula: see text] and NIRS signals for different O2 delivery conditions (blood flow, arterial O2 content) in muscle at rest (T1, T2) and during contraction (T3). Furthermore, computational analysis indicates that for adequate O2 delivery, Mb contribution to NIRS signals was significant (20%-30%) even in the presence of a linear [Formula: see text]-NIRS relationship; for a reduced O2 delivery the nonlinearity of the [Formula: see text]-NIRS relationship was related to the Mb contribution (50%). In this case (T3), the deviation from linearity is observed when O2 delivery is reduced from 1.3 to 0.7 L kg-1·min-1 ([Formula: see text] < 10 mLO2 100 mL-1) and Mb saturation decreased from 85% to 40% corresponding to an increase of the Mb contribution to ΔHHbMbN from 15% to 50% and the contribution to ΔHbMbO2,N from 0% to 30%. In contrast to a common assumption, our model indicates that both NIRS signals (ΔHHbMbN and ΔHbMbO2,N are significantly affected by Hb and Mb oxygenation changes.NEW & NOTEWORTHY Within the near-infrared spectroscopy (NIRS) signal, the contribution from hemoglobin is indistinguishable from that of myoglobin. A computation analysis indicates that a linear relationship between muscle venous oxygen content and NIRS signals does not necessarily indicate a negligible myoglobin contribution to the NIRS signal. A reduced oxygen delivery increases the myoglobin contribution to the NIRS signal. The integrative approach proposed is a powerful way to assist in interpreting the elements from which the NIRS signals are derived.

Relating cardiorespiratory responses to work rate during incremental ramp exercise on treadmill in children and adolescents: sex and age differences.

PURPOSE: Evaluation of cardiopulmonary exercise testing (CPET) slopes such as [Formula: see text] (cardiac/skeletal muscle function) and [Formula: see text] (O2 delivery/utilization), using treadmill protocols is limited because the difficulties in measuring the total work rate ([Formula: see text]). To overcome this limitation, we proposed a new method in quantifying [Formula: see text] to determine CPET slopes. METHODS: CPET's were performed by healthy patients, (n = 674, 9-18 year) 300 female (F) and 374 male (M), using an incremental ramp protocol on a treadmill. For this protocol, a quantitative relationship based on biomechanical principles of human locomotion, was used to quantify the [Formula: see text] of the subject. CPET slopes were determined by linear regression of the data recorded until the gas exchange threshold occurred. RESULTS: The method to estimate [Formula: see text] was substantiated by verifying that: [Formula: see text] for treadmill exercise corresponded to an efficiency of muscular work similar to that of cycle ergometer; [Formula: see text] (mL min-1 W-1) was invariant with age and greater in M than F older than 12 years old (13-14 years: 9.6 ± 1.5(F) vs. 10.5 ± 1.8(M); 15-16 years: 9.7 ± 1.7(F) vs. 10.6 ± 2.2(M); 17-18 years: 9.6 ± 1.7(F) vs. 11.0 ± 2.3(M), p < 0.05); similar to cycle ergometer exercise, [Formula: see text] was inversely related to body weight (BW) (r = 0.71) or [Formula: see text] (r = 0.66) and [Formula: see text] was not related to BW (r = - 0.01), but had a weak relationship with [Formula: see text] (r = 0.28). CONCLUSION: The proposed approach can be used to estimate [Formula: see text] and quantify CPET slopes derived from incremental ramp protocols at submaximal exercise intensities using the treadmill, like the cycle ergometer, to infer cardiovascular and metabolic function in both healthy and diseased states.

Mitochondrial Utilization of Competing Fuels Is Altered in Insulin Resistant Skeletal Muscle of Non-obese Rats (Goto-Kakizaki).

AIM: Insulin-resistant skeletal muscle is characterized by metabolic inflexibility with associated alterations in substrate selection, mediated by peroxisome-proliferator activated receptor δ (PPARδ). Although it is established that PPARδ contributes to the alteration of energy metabolism, it is not clear whether it plays a role in mitochondrial fuel competition. While nutrient overload may impair metabolic flexibility by fuel congestion within mitochondria, in absence of obesity defects at a mitochondrial level have not yet been excluded. We sought to determine whether reduced PPARδ content in insulin-resistant rat skeletal muscle of a non-obese rat model of T2DM (Goto-Kakizaki, GK) ameliorate the inhibitory effect of fatty acid (i.e., palmitoylcarnitine) on mitochondrial carbohydrate oxidization (i.e., pyruvate) in muscle fibers. METHODS: Bioenergetic function was characterized in oxidative soleus (S) and glycolytic white gastrocnemius (WG) muscles with measurement of respiration rates in permeabilized fibers in the presence of complex I, II, IV, and fatty acid substrates. Mitochondrial content was measured by citrate synthase (CS) and succinate dehydrogenase activity (SDH). Western blot was used to determine protein expression of PPARδ, PDK isoform 2 and 4. RESULTS: CS and SDH activity, key markers of mitochondrial content, were reduced by ∼10-30% in diabetic vs. control, and the effect was evident in both oxidative and glycolytic muscles. PPARδ (p < 0.01), PDK2 (p < 0.01), and PDK4 (p = 0.06) protein content was reduced in GK animals compared to Wistar rats (N = 6 per group). Ex vivo respiration rates in permeabilized muscle fibers determined in the presence of complex I, II, IV, and fatty acid substrates, suggested unaltered mitochondrial bioenergetic function in T2DM muscle. Respiration in the presence of pyruvate was higher compared to palmitoylcarnitine in both animal groups and fiber types. Moreover, respiration rates in the presence of both palmitoylcarnitine and pyruvate were reduced by 25 ± 6% (S), 37 ± 6% (WG) and 63 ± 6% (S), 57 ± 8% (WG) compared to pyruvate for both controls and GK, respectively. The inhibitory effect of palmitoylcarnitine on respiration was significantly greater in GK than controls (p < 10-3). CONCLUSION: With competing fuels, the presence of fatty acids diminishes mitochondria ability to utilize carbohydrate derived substrates in insulin-resistant muscle despite reduced PPARδ content.

Experiments and modeling of mine soil inertization through mechano-chemical processing: from bench to pilot scale using attritor and impact mills.

Mechano-chemical treatment has been recognized to be a promising technology for the immobilization of heavy metals (HMs) in contaminated soils without the use of additional reagents. Despite this, very few studies aiming to investigate the applicability of this technology at full scale have been published so far. In this study, a quantitative approach was developed to provide process design information to scale-up from laboratory- into pilot-scale mechano-chemical reactors for immobilizing heavy metals in contaminated mining soil. In fact, after preliminary experiments with laboratory-scale ball mills, experiments have been carried out by taking advantage of milling devices suited for pilot-scale applications. The experimental data of this work, along with literature ones, have been quantitatively interpreted by means of a mathematical model allowing to describe the effect of milling dynamics on the HM immobilization kinetics for applications at different scales. The results suggest that the mechanical process can trigger specific physico-chemical phenomena leading to a significant reduction of HMs leached from mining soils. Specifically, after suitably prolonged processing time, HM concentration in the leachate is lowered below the corresponding threshold limits. The observed behavior is well captured by the proposed model for different HMs and operating conditions. Therefore, the model might be exploited to infer design parameters for the implementation of this technique at the pilot and full scale. Moreover, it represents a valuable tool for designing and controlling mechano-chemical reactors at productive scale.

Alterations of skeletal muscle bioenergetics in a mouse with F508del mutation leading to a cystic fibrosis-like condition.

High energy expenditure is reported in cystic fibrosis (CF) animal models and patients. Alterations in skeletal muscle oxidative capacity, fuel utilization, and the creatine kinase-phosphocreatine system suggest mitochondrial dysfunction. Studies were performed on congenic C57BL/6J and F508del (Cftrtm1kth) mice. Indirect calorimetry was used to measure gas exchange to evaluate aerobic capacity during treadmill exercise. The bioenergetic function of skeletal muscle subsarcolemmal (SSM) and interfibrillar mitochondria (IFM) was evaluated using an integrated approach combining measurement of the rate of oxidative phosphorylation by polarography and of electron transport chain activities by spectrophotometry. CF mice have reduced maximal aerobic capacity. In SSM of these mice, oxidative phosphorylation was impaired in the presence of complex I, II, III, and IV substrates except when glutamate was used as substrate. This impairment appeared to be caused by a defect in complex V activity, whereas the oxidative system of the electron transport chain was unchanged. In IFM, oxidative phosphorylation and electron transport chain activities were preserved, whereas complex V activity was reduced, in CF. Furthermore, creatine kinase activity was reduced in both SSM and IFM of CF skeletal muscle. The decreased complex V activity in SSM resulted in reduced oxidative phosphorylation, which could explain the reduced skeletal muscle response to exercise in CF mice. The decrease in mitochondrial creatine kinase activity also contributed to this poor exercise response.

Isolation of mitochondrial subpopulations from skeletal muscle: Optimizing recovery and preserving integrity.

AIM: The subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria in skeletal muscle appear to have distinct biochemical properties affecting metabolism in health and disease. The isolation of mitochondrial subpopulations has been a long-time challenge while the presence of a continuous mitochondrial reticulum challenges the view of distinctive SSM and IFM bioenergetics. Here, a comprehensive approach is developed to identify the best conditions to separate mitochondrial fractions. METHODS: The main modifications to the protocol to isolate SSM and IFM from rat skeletal muscle were: (a) decreased dispase content and homogenization speed; (b) trypsin treatment of SSM fractions; (c) recentrifugation of mitochondrial fractions at low speed to remove subcellular components. To identify the conditions preserving mitochondrial function, integrity, and maximizing their recovery, microscopy (light and electron) were used to monitor effectiveness and efficiency in separating mitochondrial subpopulations while respiratory and enzyme activities were employed to evaluate function, recovery, and integrity. RESULTS: With the modifications described, the total mitochondrial yield increased with a recovery of 80% of mitochondria contained in the original skeletal muscle sample. The difference between SSM and IFM oxidative capacity (10%) with complex-I substrate was significant only with a saturated ADP concentration. The inner and outer membrane damage for both subpopulations was <1% and 8%, respectively, while the respiratory control ratio was 16. CONCLUSION: Using a multidisciplinary approach, conditions were identified to maximize SSM and IFM recovery while preserving mitochondrial integrity, biochemistry, and morphology. High quality and recovery of mitochondrial subpopulations allow to study the relationship between these organelles and disease.

Defects in skeletal muscle subsarcolemmal mitochondria in a non-obese model of type 2 diabetes mellitus.

Skeletal muscle resistance to insulin is related to accumulation of lipid-derived products, but it is not clear whether this accumulation is caused by skeletal muscle mitochondrial dysfunction. Diabetes and obesity are reported to have a selective effect on the function of subsarcolemmal and interfibrillar mitochondria in insulin-resistant skeletal muscle. The current study investigated the role of the subpopulations of mitochondria in the pathogenesis of insulin resistance in the absence of obesity. A non-obese spontaneous rat model of type 2 diabetes mellitus, (Goto-Kakizaki), was used to evaluate function and biochemical properties in both populations of skeletal muscle mitochondria. In subsarcolemmal mitochondria, minor defects are observed whereas in interfibrillar mitochondria function is preserved. Subsarcolemmal mitochondria defects characterized by a mild decline of oxidative phosphorylation efficiency are related to ATP synthase and structural alterations of inner mitochondria membrane but are considered unimportant because of the absence of defects upstream as shown with polarographic and spectrophometric assays. Fatty acid transport and oxidation is preserved in both population of mitochondria, whereas palmitoyl-CoA increased 25% in interfibrillar mitochondria of diabetic rats. Contrary to popular belief, these data provide compelling evidence that mitochondrial function is unaffected in insulin-resistant skeletal muscle from T2DM non-obese rats.

Gender differences in V˙O2 and HR kinetics at the onset of moderate and heavy exercise intensity in adolescents.

The majority of the studies on V˙O2 kinetics in pediatric populations investigated gender differences in prepubertal children during submaximal intensity exercise, but studies are lacking in adolescents. The purpose of this study was to test the hypothesis that gender differences exist in the V˙O2 and heart rate (HR) kinetic responses to moderate (M) and heavy (H) intensity exercise in adolescents. Twenty-one healthy African-American adolescents (9 males, 15.8 ± 1.1 year; 12 females, 15.7 ± 1 year) performed constant work load exercise on a cycle ergometer at M and H. The V˙O2 kinetics of the male group was previously analyzed (Lai et al., Appl. Physiol. Nutr. Metab. 33:107-117, 2008b). For both genders, V˙O2 and HR kinetics were described with a single exponential at M and a double exponential at H. The fundamental time constant (τ1) of V˙O2 was significantly higher in female than male at M (45 ± 7 vs. 36 ± 11 sec, P < 0.01) and H (41 ± 8 vs. 29 ± 9 sec, P < 0.01), respectively. The functional gain (G1) was not statistically different between gender at M and statistically higher in females than males at H: 9.7 ± 1.2 versus 10.9 ± 1.3 mL min-1 W-1, respectively. The amplitude of the slow component was not significantly different between genders. The HR kinetics were significantly (τ1, P < 0.01) slower in females than males at M (61 ± 16 sec vs. 45 ± 20 sec, P < 0.01) and H (42 ± 10 sec vs. 30 ± 8 sec, P = 0.03). The G1 of HR was higher in females than males at M: 0.53 ± 0.11 versus 0.98 ± 0.2 bpm W-1 and H: 0.40 ± 0.11 versus 0.73 ± 0.23 bpm W-1, respectively. Gender differences in the V˙O2 and HR kinetics suggest that oxygen delivery and utilization kinetics of female adolescents differ from those in male adolescents.

Mitochondrial function assessed by 31P MRS and BOLD MRI in non-obese type 2 diabetic rats.

The study aims to characterize age-associated changes in skeletal muscle bioenergetics by evaluating the response to ischemia-reperfusion in the skeletal muscle of the Goto-Kakizaki (GK) rats, a rat model of non-obese type 2 diabetes (T2D). (31)P magnetic resonance spectroscopy (MRS) and blood oxygen level-dependent (BOLD) MRI was performed on the hindlimb of young (12 weeks) and adult (20 weeks) GK and Wistar (control) rats. (31)P-MRS and BOLD-MRI data were acquired continuously during an ischemia and reperfusion protocol to quantify changes in phosphate metabolites and muscle oxygenation. The time constant of phosphocreatine recovery, an index of mitochondrial oxidative capacity, was not statistically different between GK rats (60.8 ± 13.9 sec in young group, 83.7 ± 13.0 sec in adult group) and their age-matched controls (62.4 ± 11.6 sec in young group, 77.5 ± 7.1 sec in adult group). During ischemia, baseline-normalized BOLD-MRI signal was significantly lower in GK rats than in their age-matched controls. These results suggest that insulin resistance leads to alterations in tissue metabolism without impaired mitochondrial oxidative capacity in GK rats.

Chronic hindlimb suspension unloading markedly decreases turnover rates of skeletal and cardiac muscle proteins and adipose tissue triglycerides.

We previously showed that a single bolus of "doubly-labeled" water ((2)H2 (18)O) can be used to simultaneously determine energy expenditure and turnover rates (synthesis and degradation) of tissue-specific lipids and proteins by modeling labeling patterns of protein-bound alanine and triglyceride-bound glycerol (Bederman IR, Dufner DA, Alexander JC, Previs SF. Am J Physiol Endocrinol Metab 290: E1048-E1056, 2006). Using this novel method, we quantified changes in the whole body and tissue-specific energy balance in a rat model of simulated "microgravity" induced by hindlimb suspension unloading (HSU). After chronic HSU (3 wk), rats exhibited marked atrophy of skeletal and cardiac muscles and significant decrease in adipose tissue mass. For example, soleus muscle mass progressively decreased 11, 43, and 52%. We found similar energy expenditure between control (90 ± 3 kcal · kg(-1)· day(-1)) and hindlimb suspended (81 ± 6 kcal/kg day) animals. By comparing food intake (∼ 112 kcal · kg(-1) · day(-1)) and expenditure, we found that animals maintained positive calorie balance proportional to their body weight. From multicompartmental fitting of (2)H-labeling patterns, we found significantly (P < 0.005) decreased rates of synthesis (percent decrease from control: cardiac, 25.5%; soleus, 70.3%; extensor digitorum longus, 44.9%; gastrocnemius, 52.5%; and adipose tissue, 39.5%) and rates of degradation (muscles: cardiac, 9.7%; soleus, 52.0%; extensor digitorum longus, 27.8%; gastrocnemius, 37.4%; and adipose tissue, 50.2%). Overall, HSU affected growth of young rats by decreasing the turnover rates of proteins in skeletal and cardiac muscles and adipose tissue triglycerides. Specifically, we found that synthesis rates of skeletal and cardiac muscle proteins were affected to a much greater degree compared with the decrease in degradation rates, resulting in large negative balance and significant tissue loss. In contrast, we found a small decrease in adipose tissue triglyceride synthesis paired with a large decrease in degradation, resulting in smaller negative energy balance and loss of fat mass. We conclude that HSU in rats differentially affects turnover of muscle proteins vs. adipose tissue triglycerides.

Relating tissue/organ energy expenditure to metabolic fluxes in mouse and human: experimental data integrated with mathematical modeling.

Mouse models of human diseases are used to study the metabolic and physiological processes leading to altered whole-body energy expenditure (EE), which is the sum of EE of all body organs and tissues. Isotopic techniques, arterio-venous difference of substrates, oxygen, and blood flow measurements can provide essential information to quantify tissue/organ EE and substrate oxidation. To complement and integrate experimental data, quantitative mathematical model analyses have been applied in the design of experiments and evaluation of metabolic fluxes. In this study, a method is presented to quantify the energy expenditure of the main mouse organs using metabolic flux measurements. The metabolic fluxes and substrate utilization of the main metabolic pathways of energy metabolism in the mouse tissue/organ systems and the whole body are quantified using a mathematical model based on mass and energy balances. The model is composed of six organ/tissue compartments: brain, heart, liver, gastrointestinal tract, muscle, and adipose tissue. Each tissue/organ is described with a distinct system of metabolic reactions. This model quantifies metabolic and energetic characteristics of mice under overnight fasting conditions. The steady-state mass balances of metabolites and energy balances of carbohydrate and fat are integrated with available experimental data to calculate metabolic fluxes, substrate utilization, and oxygen consumption in each tissue/organ. The model serves as a paradigm for designing experiments with the minimal reliable measurements necessary to quantify tissue/organs fluxes and to quantify the contributions of tissue/organ EE to whole-body EE that cannot be easily determined currently.

Exercise training decreases activation of the mitochondrial fission protein dynamin-related protein-1 in insulin-resistant human skeletal muscle.

Defects in mitochondrial dynamics, the processes of fission, fusion, and mitochondrial autophagy, may contribute to metabolic disease including type 2 diabetes. Dynamin-related protein-1 (Drp1) is a GTPase protein that plays a central role in mitochondrial fission. We hypothesized that aerobic exercise training would decrease Drp1 Ser(616) phosphorylation and increase fat oxidation and insulin sensitivity in obese (body mass index: 34.6 ± 0.8 kg/m(2)) insulin-resistant adults. Seventeen subjects performed supervised exercise for 60 min/day, 5 days/wk at 80-85% of maximal heart rate for 12 wk. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp, and fat oxidation was determined by indirect calorimetry. Skeletal muscle biopsies were obtained from the vastus lateralis muscle before and after the 12-wk program. The exercise intervention increased insulin sensitivity 2.1 ± 0.2-fold (P < 0.01) and fat oxidation 1.3 ± 0.3-fold (P < 0.01). Phosphorylation of Drp1 at Ser(616) was decreased (pre vs. post: 0.81 ± 0.15 vs. 0.58 ± 0.14 arbitrary units; P < 0.05) following the intervention. Furthermore, reductions in Drp1 Ser(616) phosphorylation were negatively correlated with increases in fat oxidation (r = -0.58; P < 0.05) and insulin sensitivity (rho = -0.52; P < 0.05). We also examined expression of genes related to mitochondrial dynamics. Dynamin1-like protein (DNM1L; P < 0.01), the gene that codes for Drp1, and Optic atrophy 1 (OPA1; P = 0.05) were significantly upregulated following the intervention, while there was a trend towards an increase in expression of both mitofusin protein MFN1 (P = 0.08) and MFN2 (P = 0.07). These are the first data to suggest that lifestyle-mediated improvements in substrate metabolism and insulin sensitivity in obese insulin-resistant adults may be regulated through decreased activation of the mitochondrial fission protein Drp1.

Functional abdominal wall reconstruction improves core physiology and quality-of-life.

INTRODUCTION: One of the goals of modern ventral hernia repair (VHR) is restoring the linea alba by returning the rectus muscles to the midline. Although this practice presumably restores native abdominal wall function, improvement of abdominal wall function has never been measured in a scientific fashion. We hypothesized that a dynamometer could be used to demonstrate an improvement in rectus muscle function after open VHR with restoration of the midline, and that this improvement would be associated with a better quality-of-life. METHODS: Thirteen patients agreed to dynamometric analysis before and 6 months after an open posterior component separation (Rives-Stoppa technique complimented with a transversus abdominis muscle release) and mesh sublay. Analysis done using a dynamometer (Biodex 3, Corp, Shirley, NY) included measurement of peak torque (PT; N*m) and PT per bodyweight (BW; %) generated during abdominal flexion in 5 settings: Isokinetic analysis at 45°/s and 60°/s as well as isometric analysis at 0°, -15°, and +15°. Power (W) was calculated during isokinetic settings. Quality-of-life was measured using our validated HerQles survey at the time of each dynamometric analysis. RESULTS: Thirteen patients (mean age, 54 ± 9 years; mean body mass index, 31 ± 7 kg/m(2)) underwent repair with restoration of the midline using the aforementioned technique. Mean hernia width was 12.5 cm (range, 5-19). Improvements in PT and PT/BW were significant in all 5 settings (P < .05). Improvement in power during isokinetic analyses at 45°/s and 60°/s was also significant (P < .05). All patients reported an improvement in quality-of-life, which was associated positively with each dynamometric parameter. CONCLUSION: Restoration of the linea alba during VHR is associated with improved abdominal wall functionality. Analysis of rectus muscle function using a dynamometer showed statistical improvement by isokinetic and isometric measurements, all of which were associated with an improvement in quality-of-life.

An online model composition tool for system biology models.

BACKGROUND: There are multiple representation formats for Systems Biology computational models, and the Systems Biology Markup Language (SBML) is one of the most widely used. SBML is used to capture, store, and distribute computational models by Systems Biology data sources (e.g., the BioModels Database) and researchers. Therefore, there is a need for all-in-one web-based solutions that support advance SBML functionalities such as uploading, editing, composing, visualizing, simulating, querying, and browsing computational models. RESULTS: We present the design and implementation of the Model Composition Tool (Interface) within the PathCase-SB (PathCase Systems Biology) web portal. The tool helps users compose systems biology models to facilitate the complex process of merging systems biology models. We also present three tools that support the model composition tool, namely, (1) Model Simulation Interface that generates a visual plot of the simulation according to user's input, (2) iModel Tool as a platform for users to upload their own models to compose, and (3) SimCom Tool that provides a side by side comparison of models being composed in the same pathway. Finally, we provide a web site that hosts BioModels Database models and a separate web site that hosts SBML Test Suite models. CONCLUSIONS: Model composition tool (and the other three tools) can be used with little or no knowledge of the SBML document structure. For this reason, students or anyone who wants to learn about systems biology will benefit from the described functionalities. SBML Test Suite models will be a nice starting point for beginners. And, for more advanced purposes, users will able to access and employ models of the BioModels Database as well.

Distinguishing the effects of convective and diffusive O2 delivery on VO2 on-kinetics in skeletal muscle contracting at moderate intensity.

With current techniques, experimental measurements alone cannot characterize the effects of oxygen blood-tissue diffusion on muscle oxygen uptake (Vo2) kinetics in contracting skeletal muscle. To complement experimental studies, a computational model is used to quantitatively distinguish the contributions of convective oxygen delivery, diffusion into cells, and oxygen utilization to Vo2 kinetics. The model is validated using previously published experimental Vo2 kinetics in response to slowed blood flow (Q) on-kinetics in canine muscle (τQ = 20 s, 46 s, and 64 s) [Goodwin ML, Hernández A, Lai N, Cabrera ME, Gladden LB. J Appl Physiol. 112:9-19, 2012]. Distinctive effects of permeability-surface area or diffusive conductance (PS) and Q on Vo2 kinetics are investigated. Model simulations quantify the relationship between PS and Q, as well as the effects of diffusion associated with PS and Q dynamics on the mean response time of Vo2. The model indicates that PS and Q are linearly related and that PS increases more with Q when convective delivery is limited by slower Q dynamics. Simulations predict that neither oxygen convective nor diffusive delivery are limiting Vo2 kinetics in the isolated canine gastrocnemius preparation under normal spontaneous conditions during transitions from rest to moderate (submaximal) energy demand, although both operate close to the tipping point.

Computational Model of Cellular Metabolic Dynamics in Skeletal Muscle Fibers during Moderate Intensity Exercise.

Human skeletal muscles have different fiber types with distinct metabolic functions and physiological properties. The quantitative metabolic responses of muscle fibers to exercise provide essential information for understanding and modifying the regulatory mechanisms of skeletal muscle. Since in vivo data from skeletal muscle during exercise is limited, a computational, physiologically based model has been developed to quantify the dynamic metabolic responses of many key chemical species. This model distinguishes type I and II muscle fibers, which share the same blood supply. An underlying hypothesis is that the recruitment and metabolic activation of the two main types of muscle fibers differ depending on the pre-exercise state and exercise protocols. Here, activation measured by metabolic response (or enzymatic activation) in single fibers is considered linked but distinct from fiber recruitment characterized by the number (or mass) of each fiber type involved during a specific exercise. The model incorporates species transport processes between blood and muscle fibers and most of the important reactions/pathways in cytosol and mitochondria within each fiber type. Model simulations describe the dynamics of intracellular species concentrations and fluxes in muscle fibers during moderate intensity exercise according to various experimental protocols and conditions. This model is validated by comparing model simulations with experimental data in single muscle fibers and in whole muscle. Model simulations demonstrate that muscle-fiber recruitment and metabolic activation patterns in response to exercise produce significantly distinctive effects depending on the exercise conditions.