Similar maximal aerobic capacity but lower energy efficiency during low-to-moderate exercise in women with constitutional thinness: new results from the NUTRILEAN study.

PURPOSE: Individuals with constitutional thinness have been presented with a lower muscular energy metabolism at the cellular level but their effective aerobic capacities and exercise-related energy efficiency remains unexplored. The present study compares maximal and sub-maximal aerobic capacities between subjects with constitutional thinness and age-matched normal-weight ones. METHODS: Anthropometric measures, body composition (Dual-X-ray absorptiometry), physical activity and sedentary time (GT3x actigraphs), and maximal aerobic capacities (cycling V ˙ O 2peak test) were assessed in 18 constitutionally thin (CT-body mass index < 17.5 kg m-2) and 17 normal-weight (NW-body mass index between 20 and 25 kg m-2) women. Energy efficiency was assessed during a submaximal cycling test and a walking exercise. RESULTS: CT had a lower body mass and body mass index compared to NW. Absolute peak oxygen uptake and maximal aerobic power were lower in CT subjects compared to NW (ES: - 1.63 [- 2.40; - 0.86] and - 1.32 [- 2.05; - 0.58], p < 0.001). V ˙ O 2peak related to body mass was not different between groups. Gross and net efficiency (ES: - 0.78 [- 1.48; - 0.06], p = 0.03 and ES: - 0.73 [- 1.43; - 0.01], p = 0.05) were lower in CT compared to NW during the submaximal cycling exercise. The gross energy cost of walking related to body mass was lower in subjects with CT (ES: - 1.80 [- 2.60; - 0.97, p = 0.05), with no difference for the net one. Perceived exertion was similar between groups in responses to both submaximal exercises. CONCLUSION: Constitutionally thin women do not show impaired aerobic capacities at moderate to maximal intensities despite lower energy efficiency while cycling and walking at low-to-moderate intensities.

The hamstrings are more impacted than the quadriceps after severe ankle sprain.

Ankle sprains (AS) are common in the military population, with a prevalence 5 to 8 times higher than that for civilians. The aim of this study was to evaluate in patients with severe AS the impact of disuse on thigh muscle induced by unloading and immobilization due to care. This study focused on muscle trophicity and dynamometric strength. In this observational prospective study, assessments were repeated at 3 visits: close to injury, 15 and 30 days following the sprain. The injured limb was compared to the contralateral limb. A dynamometer assessment was used to monitor changes in strength and fatigue of the thigh muscles of both limbs. Isometric and isokinetic concentric evaluation of peak torque (PTiso and PTdyn), total work (Wt), and peak torque time integral (IPT) of thigh muscles. Full follow-up was obtained in 30 subjects. The injured limbs showed significant deficits in the mean (SD). The quadriceps PTiso and IPT deficits were -12.6% ± 1.9% (P < .0001) and -13.27% ± 1.8% (P < .0001), respectively. The quadriceps PTdyn showed a significant deficit since V2 (-12.2.5% ± 2.0). The quadriceps Wt presented a significant deficit of -4.2% ± 2.4 (P < .0007) at 1 month. The hamstring PTdyn deficit presented a mean loss of -16.5% ± 2.4% (P < .0001). The hamstring Wt deficit was -13.7% ± 2.3% (P < .001). The analysis of variance showed that the grade of the sprain had a significant effect on the quadriceps PTq deficit (P < .016) but not the type of discharge. Our study showed that disuse leads to a significant deficit in the strength of knee muscles within 1 month. It is noteworthy that the hamstrings are more affected than the quadriceps. The rehabilitation protocol to prevent the risk of iterative ankle injuries and secondary knee injuries should incorporate early training of both quadriceps and hamstrings.

Association of protein-energy partitioning with body weight and body composition changes in adolescents with severe obesity.

BACKGROUND/OBJECTIVES: Body composition and protein-energy partitioning changes are important factors of body weight regulation, but have not been studied in the context of clinical obesity treatment setting. Thus, the aim of the present study was to investigate the pattern of body weight loss, body composition, and energy partitioning changes during a 9-month multidisciplinary weight loss program and 4-month follow up and to test the associations among these changes in adolescents with severe obesity. SUBJECTS/METHODS: Twenty-five adolescents (14.1 ± 1.5 years old; 13 girls) with severe obesity joined a pediatric obesity center for a 9-month inpatient multidisciplinary weight loss program. All participants performed body composition assessment (i.e. fat mass-FM, and fat-free mass-FFM) and completed a 36-h session in indirect calorimetric chamber before the start (T0), at the end of the intervention (T1) and 4 months follow-up to the intervention (T2). The protein-energy partitioning (P ratio) was calculated as urinary nitrogen loss/total energy expenditure over 24 hours. INTERVENTIONS: 9-month individualized multidisciplinary weight loss program consisting of lifestyle education, psychological support, physical activity, and dietary intervention. RESULTS: Initial P ratio was positively associated with changes in body weight from T0 to T1 (p = 0.038). The changes in FFM/FM were negatively associated with body weight changes in boys (p = 0.006) from T0 to T1 and in girls (p < 0.001) from T1 to T2. Urinary nitrogen excretion (p < 0.001) and total energy expenditure (p < 0.001) significantly decreased during the weight loss program while the P ratio did not significantly change. CONCLUSION: The present results suggest that baseline and changes in energy partitioning may be associated with changes in body weight in adolescents with severe obesity. In addition, sexual dimorphism in these patterns of change suggest the need for specific dietary and physical activity strategies in boys and girls to optimize body weight loss and to prevent or slow weight regain.

Systematic Review of COVID-19-Related Physical Activity-Based Rehabilitations: Benefits to Be Confirmed by More Robust Methodological Approaches.

The first emergency was to receive and treat COVID-19 patients in their acute phase; today, there is a clear need to propose appropriate post-acute rehabilitation programs. The aim of this research was to systematically review the effects of physical activity programs in the recovery of post-COVID-19 patients. The literature search followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, was registered in the PROSPERO database (CRD42022289219), and was conducted between August and December 2021. A total of 35 studies out of the 1528 initially identified were finally included in the analysis. The systematic review clearly showed the health benefits of rehabilitation including physical activity in post-COVID-19 recovery, regardless of exercise modalities. These positive results were even observed using minor muscle re-mobilization for severe cases (i.e., postural changes, few steps-2 times/day) or using low volumes of exercise for mild-to-moderate cases (i.e., 120 min/week). A total of 97% of the 29 studies that performed statistical analyses demonstrated a significant increase in at least one parameter of functional capacity, and 96% of the 26 studies that statistically investigated the effects on the quality of life, mental health, and general state reported improvements. Yet, most of the studies were retrospective, uncontrolled, and enrolled aged people with comorbidities presented in severe forms of COVID-19. Physical activity programs, in addition to their high heterogeneity, remained poorly described in 83% of the studies and were part of a multidisciplinary program for 89% of the studies. Despite promising results, there is today a real need for prospective well-designed studies specifically assessing the effects of physical activity. In addition, it might appear relevant to propose standardized programs further considering the main characteristics of patients such as age, comorbidities, or the severity of COVID-19.

Muscle Contractile Characteristics During Exhaustive Dynamic Exercise and Recovery.

Our aim was to provide an in vivo assessment of human muscle twitch characteristics during and following an exhaustive dynamic exercise to explore temporal alterations of the rate of force development (RFD) and relaxation (RFR). Eleven healthy participants (mean age ± SD: 24 ± 3 years) completed a dynamic knee-extensor exercise in randomized order at three different intensities, eliciting exhaustion after ∼9 min (56 ± 10 W), ∼6 min (60 ± 10 W), and ∼4 min (63 ± 10 W), in addition to a low-intensity (28 ± 5 W) bout. In a novel setup, an electrical doublet stimulation of m. vastus lateralis was applied during exercise (every 30 s) and recovery for frequent evaluation of key contractile properties (maximal force, RFD, RFR, and electromechanical delay) in addition to M-wave characteristics. RFD and RFR remained stable throughout the low-intensity trial but declined in all exhaustive trials to reach a similar level of ∼40% of pre-exercise values at task failure but with the exponential decay augmented by intensity. Following exhaustion, there was a fast initial recovery of RFD and RFR to ∼80% of pre-exercise values within 1 min, followed by a longer suppression at this level. The M-wave characteristics remained unchanged during all trials. In conclusion, this is the first study to quantify the intensity-dependent alterations of RFD and RFR during and after exhaustive dynamic exercise in humans. A hypothesized reduction and fast reversion of RFD was confirmed, and a surprising compromised RFR is reported. The present unique experimental approach allows for novel insight to exercise-induced alterations in human muscle contractile properties which is relevant in health and disease.

The ratio of maximal handgrip force and maximal cycloergometry power as a diagnostic tool to screen for metabolic myopathies.

Metabolic myopathies comprise a diverse group of inborn errors of intermediary metabolism affecting skeletal muscle, and often present clinically as an inability to perform normal exercise. Our aim was to use the maximal mechanical performances achieved during two functional tests, isometric handgrip test and cycloergometer, to identify metabolic myopathies among patients consulting for exercise-induced myalgia. Eighty-three patients with exercise-induced myalgia and intolerance were evaluated, with twenty-three of them having a metabolic myopathy (McArdle, n = 9; complete myoadenylate deaminase deficiency, n = 10; respiratory chain deficiency, n = 4) and sixty patients with non-metabolic myalgia. In all patients, maximal power (MP) was determined during a progressive exercise test on a cycloergometer and maximal voluntary contraction force (MVC) was assessed using a handgrip dynamometer. The ratio between percent-predicted values for MVC and MP was calculated for each subject (MVC%pred:MP%pred ratio). In patients with metabolic myopathy, the MVC%pred:MP%pred ratio was significantly higher compared to non-metabolic myalgia (1.54 ± 0.62 vs. 0.92 ± 0.25; p < 0.0001). ROC analysis of MVC%pred:MP%pred ratio showed AUC of 0.843 (0.758-0.927, 95% CI) for differentiating metabolic myopathies against non-metabolic myalgia. The optimum cutoff was taken as 1.30 (se = 69.6%, sp = 96.7%), with a corresponding diagnostic odd ratio of 66.3 (12.5-350.7, 95% CI). For a pretest probability of 15% in our tertiary reference center, the posttest probability for metabolic myopathy is 78.6% when MVC%pred:MP%pred ratio is above 1.3. In conclusion, the MVC%pred:MP%pred ratio is appropriate as a screening test to distinguish metabolic myopathies from non-metabolic myalgia.

Exercise efficiency impairment in metabolic myopathies.

Metabolic myopathies are muscle disorders caused by a biochemical defect of the skeletal muscle energy system resulting in exercise intolerance. The primary aim of this research was to evaluate the oxygen cost (∆V'O2/∆Work-Rate) during incremental exercise in patients with metabolic myopathies as compared with patients with non-metabolic myalgia and healthy subjects. The study groups consisted of eight patients with muscle glycogenoses (one Tarui and seven McArdle diseases), seven patients with a complete and twenty-two patients with a partial myoadenylate deaminase (MAD) deficiency in muscle biopsy, five patients with a respiratory chain deficiency, seventy-three patients with exercise intolerance and normal muscle biopsy (non-metabolic myalgia), and twenty-eight healthy controls. The subjects underwent a cardiopulmonary exercise test (CPX Medgraphics) performed on a bicycle ergometer. Pulmonary V'O2 was measured breath-by-breath throughout the incremental test. The ∆V'O2/∆Work-Rate slope for exercise was determined by linear regression analysis. Lower oxygen consumption (peak percent of predicted, mean ± SD; p < 0.04, one-way ANOVA) was seen in patients with glycogenoses (62.8 ± 10.2%) and respiratory chain defects (70.8 ± 23.3%) compared to patients with non-metabolic myalgia (100.0 ± 15.9%) and control subjects (106.4 ± 23.5%). ∆V'O2/∆Work-Rate slope (mLO2.min-1.W-1) was increased in patients with MAD absent (12.6 ± 1.5), MAD decreased (11.3 ± 1.1), glycogenoses (14.0 ± 2.5), respiratory chain defects (13.1 ± 1.2), and patients with non-metabolic myalgia (11.3 ± 1.3) compared with control subjects (10.2 ± 0.7; p < 0.001, one-way ANOVA). In conclusion, patients with metabolic myopathies display an increased oxygen cost during exercise and therefore can perform less work for a given VO2 consumption during daily life-submaximal exercises.

Monitoring Muscle Fatigue Progression during Dynamic Exercise.

PURPOSE: To develop and validate a novel model for assessment of peripheral fatigue progression during dynamic exercise. METHODS: Seven males and four females (24 ± 3 yr) completed one-legged knee-extensor exercise at 40% of peak power output (PPO) for 12 min (40% PPO). Additionally, an exhaustive bout lasting approximately 6 min (84% ± 2% PPO; 59 ± 10 W) was contrasted to two bouts completed at ±5% of the target workload. Trials were completed in randomized order. Percutaneous electrical stimulation of m. vastus lateralis during the passive knee-flexion phase allowed quantification of maximal twitch force every 30 s in parallel with RPE. RESULTS: Elicited twitch force remained unchanged during the 40% PPO trial. During the three exhaustive bouts, exercise differed in duration (561 ± 154 s, 366 ± 64 s, 245 ± 61 s; P < 0.001) and amplitude of elicited twitch force showed a curvilinear decline across time. Elicited twitch force at exhaustion was approximately 60% reduced and similar between the exhaustive trials (intraclass correlation coefficient, 0.76; 95% confidence interval, 0.48-0.92). The increase in RPE during exercise was strongly correlated to the gradually reduced evoked twitch force (repeated-measures correlation, 0.89; 95% confidence interval, 0.62-0.97). CONCLUSIONS: The developed model permits quantification of muscle fatigue progression during continuous dynamic one-legged knee-extension and a biphasic fatigue pattern is demonstrated during intense exercise. The model is sensitive to small changes in intensity, and it provides a novel approach for studying muscular mechanisms and their temporal relation to fatigue progression in vivo.

Impact of a specific training programme on the neuromodulation of pain in female patient with fibromyalgia (DouFiSport): a 24-month, controlled, randomised, double-blind protocol.

INTRODUCTION: The main symptom of fibromyalgia (FM) is diffuse pain. There is currently no aetiological treatment for FM. However, all pain associations and best practice guidelines strongly advocate the practice of aerobic physical activity to improve the symptoms of FM subjects. The mechanisms of dysfunctional pain are mostly central and related to stress axis dysfunction (autonomic nervous system and corticotropic axis). Our main objective is to assess the efficacy of a specific training programme on endogenous pain control mechanisms in female patients with FM. Further aims include rebalancing the autonomic neurovegetative system, improving quality of life and sleep quality, and reintegrating patients into society and work. METHODS AND ANALYSIS: 110 female patients with FM diagnosed on American College of Rheumatology 2010 criteria, aged 18-65 years and meeting inclusion conditions will be recruited and randomised into two groups (active and semiactive). The training programme will consist of three 45 min sessions per week of supervised, individualised physical activity over 2 years. Only the intensity of the exercises will differ between the two groups (moderate intensity vs low intensity).All outcome measures will be conducted at baseline (T0), after 6-9 months of training (T6-9) and after 24 months of training (T24). The primary endpoint will be an improvement of pain modulation (activation of diffuse noxious inhibitory control) evaluated by the stimulation test. The secondary endpoint will be relief of pain, anxiety, depression, stress, sleep disorders, pain impact on life quality, and improved heart rate, blood pressure and salivary cortisol. ETHICS AND DISSEMINATION: This study is approved by the Committee for the Protection of Persons West VI. The results will be published in specialised scientific journals and will be presented at scientific meetings on pain and/or physical activity. TRIAL REGISTRATION NUMBER: NCT02486965; Pre-results.

Effects of AMPD1 common mutation on the metabolic-chronotropic relationship: Insights from patients with myoadenylate deaminase deficiency.

PURPOSE: Current evidence indicates that the common AMPD1 gene variant is associated with improved survival in patients with advanced heart failure. Whilst adenosine has been recognized to mediate the cardioprotective effect of C34T AMPD1, the precise pathophysiologic mechanism involved remains undefined to date. To address this issue, we used cardio-pulmonary exercise testing data (CPX) from subjects with myoadenylate deaminase (MAD) defects. METHODS: From 2009 to 2013, all the patients referred in our laboratory to perform a metabolic exercise testing, i.e. a CPX with measurements of muscle metabolites in plasma during and after exercise testing, were prospectively enrolled. Subjects that also underwent an open muscle biopsy for diagnosis purpose were finally included. The metabolic-chronotropic response was assessed by calculating the slope of the linear relationship between the percent heart rate reserve and the percent metabolic reserve throughout exercise. MAD activity was measured using the Fishbein's technique in muscle biopsy sample. The common AMPD1 mutation was genotyped and the AMPD1 gene was sequenced to screen rare variants from blood DNA. RESULTS: Sixty-seven patients were included in the study; 5 had complete MAD deficiency, 11 had partial MAD deficiency, and 51 had normal MAD activity. Compared with normal MAD activity subjects, MAD deficient subjects appeared to have a lower-than-expected metabolic-chronotopic response during exercise. The metabolic-chronotropic relationship is more closely correlated with MAD activity in skeletal muscle (Rs = 0.57, p = 5.93E-7, Spearman correlation) than the presence of the common AMPD1 gene variant (Rs = 0.34, p = 0.005). Age-predicted O2 pulse ratio is significantly increased in MAD deficient subjects, indicating a greater efficiency of the cardiovascular system to deliver O2 (p < 0.01, Scheffé's post hoc test). CONCLUSION: The metabolic-chronotropic response is decreased in skeletal muscle MAD deficiency, suggesting a biological mechanism by which AMPD1 gene exerts cardiac effect.

Case-Finding for Persistent Airway Obstruction in Farmers: A Questionnaire With Optimal Diagnosis Criteria.

INTRODUCTION: Appropriate identification of subjects who are candidates for spirometry through case-finding questionnaires may help solve the problem of chronic obstructive pulmonary disease misdiagnosis. The performance of case-finding questionnaires depends at least partially on the characteristics of the population used for their development. The use of an accurate threshold for the forced expiratory volume in 1 second / forced vital capacity ratio to define persistent airway obstruction is also vital in ascertaining chronic obstructive pulmonary disease. METHODS: Using a population examined between October 2012 and May 2013 that included a large subset of agricultural workers both exposed and unexposed to tobacco smoking, the authors aimed to select a combination of items that would identify persons most likely to have persistent airway obstruction defined as forced expiratory volume in 1 second / forced vital capacity less than the lower limit of normal according to the Global Lung Initiative-2012 equations. Two thirds of the population (n=3,397) were randomly selected to develop a questionnaire, and one third (n=1,698) was reserved for questionnaire validation. Statistical analysis was performed in 2016. RESULTS: The selected items were sex, dyspnea, BMI, tobacco smoking habits, age, history of respiratory diseases, and history of occupation at risk. The C-index of the model was 0.84 (95% CI=0.80, 0.88) for the development population and 0.76 (95% CI=0.66, 0.86) for the validation population. Using the selected items in combination, the sensitivity and specificity in identifying persistent airway obstruction were 76% and 77%, respectively, in the development population (and 68% and 73%, respectively, in the validation population) for a threshold value of 2.50%. CONCLUSIONS: This seven-item questionnaire is the first developed from a population comprising a large subset of agricultural workers and using the Global Lung Initiative-2012 equations.

Single Muscle Immobilization Decreases Single-Fibre Myosin Heavy Chain Polymorphism: Possible Involvement of p38 and JNK MAP Kinases.

PURPOSE: Muscle contractile phenotype is affected during immobilization. Myosin heavy chain (MHC) isoforms are the major determinant of the muscle contractile phenotype. We therefore sought to evaluate the effects of muscle immobilization on both the MHC composition at single-fibre level and the mitogen-activated protein kinases (MAPK), a family of intracellular signaling pathways involved in the stress-induced muscle plasticity. METHODS: The distal tendon of female Wistar rat Peroneus Longus (PL) was cut and fixed to the adjacent bone at neutral muscle length. Four weeks after the surgery, immobilized and contralateral PL were dissociated and the isolated fibres were sampled to determine MHC composition. Protein kinase 38 (p38), extracellular signal-regulated kinases (ERK1/2), and c-Jun- NH2-terminal kinase (JNK) phosphorylations were measured in 6- and 15-day immobilized and contralateral PL. RESULTS: MHC distribution in immobilized PL was as follows: I = 0%, IIa = 11.8 ± 2.8%, IIx = 53.0 ± 6.1%, IIb = 35.3 ± 7.3% and I = 6.1 ± 3.9%, IIa = 22.1 ± 3.4%, IIx = 46.6 ± 4.5%, IIb = 25.2 ± 6.6% in contralateral muscle. The MHC composition in immobilized muscle is consistent with a faster contractile phenotype according to the Hill's model of the force-velocity relationship. Immobilized and contralateral muscles displayed a polymorphism index of 31.1% (95% CI 26.1-36.0) and 39.3% (95% CI 37.0-41.5), respectively. Significant increases in p38 and JNK phosphorylation were observed following 6 and 15 days of immobilization. CONCLUSIONS: Single muscle immobilization at neutral length induces a shift of MHC composition toward a faster contractile phenotype and decreases the polymorphic profile of single fibres. Activation of p38 and JNK could be a potential mechanism involved in these contractile phenotype modifications during muscle immobilization.

Prevalence and risk factors for COPD in farmers: a cross-sectional controlled study.

There are conflicting data regarding the magnitude and determinants of chronic obstructive pulmonary disease (COPD) risk in farmers.In a cross-sectional study of 917 nonfarming working controls and 3787 farmers aged 40-75 years, we assessed respiratory symptoms, tobacco exposure, job history (without direct exposure measurement) and lung function. COPD was defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criterion (post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.70) and by the Quanjer reference equation (post-bronchodilator FEV1/FVC

Diagnostic Algorithm for Glycogenoses and Myoadenylate Deaminase Deficiency Based on Exercise Testing Parameters: A Prospective Study.

AIM: Our aim was to evaluate the accuracy of aerobic exercise testing to diagnose metabolic myopathies. METHODS: From December 2008 to September 2012, all the consecutive patients that underwent both metabolic exercise testing and a muscle biopsy were prospectively enrolled. Subjects performed an incremental and maximal exercise testing on a cycle ergometer. Lactate, pyruvate, and ammonia concentrations were determined from venous blood samples drawn at rest, during exercise (50% predicted maximal power, peak exercise), and recovery (2, 5, 10, and 15 min). Biopsies from vastus lateralis or deltoid muscles were analysed using standard techniques (reference test). Myoadenylate deaminase (MAD) activity was determined using p-nitro blue tetrazolium staining in muscle cryostat sections. Glycogen storage was assessed using periodic acid-Schiff staining. The diagnostic accuracy of plasma metabolite levels to identify absent and decreased MAD activity was assessed using Receiver Operating Characteristic (ROC) curve analysis. RESULTS: The study involved 51 patients. Omitting patients with glycogenoses (n = 3), MAD staining was absent in 5, decreased in 6, and normal in 37 subjects. Lactate/pyruvate at the 10th minute of recovery provided the greatest area under the ROC curves (AUC, 0.893 ± 0.067) to differentiate Abnormal from Normal MAD activity. The lactate/rest ratio at the 10th minute of recovery from exercise displayed the best AUC (1.0) for discriminating between Decreased and Absent MAD activities. The resulting decision tree achieved a diagnostic accuracy of 86.3%. CONCLUSION: The present algorithm provides a non-invasive test to accurately predict absent and decreased MAD activity, facilitating the selection of patients for muscle biopsy and target appropriate histochemical analysis.

Tumor Necrosis Factor alpha induced hypoexcitability in rat muscle evidenced in a model of ion currents and action potential.

Sepsis and Tumor Necrosis Factor alpha (TNFα), a major pro-inflammatory mediator, have previously been shown to induce a decrease in the conductance of voltage-dependent sodium channels (NaV). Moreover, TNFα increased resting membrane potential, leading to hyperpolarization. NaV and resting potential are the two major factors of membrane excitability. Then we hypothesis that TNFα can decrease muscle membrane excitability. To evidence that role of TNFα, we carried out a simulation of the sodium and potassium currents and action potential (AP) of isolated muscle fibre. We used a computer model based on Hodgkin and Huxley equations, but also taking into account the sodium-potassium pump current. Our first aim was to optimise this model in control conditions according to our measurements of currents. Then the model was modified to fit the values measured experimentally in TNFα-containing medium in order to determine the modifications induced in the currents and hence in AP triggering. Our model provides a very good fit with experimental data on the ion currents. Moreover, it clearly shows that the triggering level of AP is increased in TNFα-containing medium, thus corresponding to a decreased excitability.

Alteration of muscle membrane excitability in sepsis: possible involvement of ciliary nervous trophic factor (CNTF).

One of the main factor involved neuromyopathy acquired in intensive care unit (ICU) appears to be sepsis. It induces the release of many pro- and anti-inflammatory factors which can directly modulate the muscle excitability. We have studied the effects of one of them: the ciliary nervous trophic factor (CNTF) which is a cytokine released in the early phase of sepsis. CNTF induces a decrease in the sodium current and an increase in resting potential as in sodium inversion potential. These effects could participate to the hypo-excitability observed during sepsis and could be involved in the ICU acquired neuromyopathy. As for TNFα, this early effect is mainly mediated by protein kinase C (PKC) activation and appears to be a reversible post-transcriptional effect.

TNFα increases resting potential in isolated fibres from rat peroneus longus by a PKC mediated mechanism: involvement in ICU acquired polyneuromyopathy.

BACKGROUND AND AIMS: Our aim was to investigate the effect of TNFα on muscle resting potential (RP) and then in muscle excitability and to demonstrate another mechanism implicated in intensive care units (ICU) acquired polyneuromyopathy. METHODS: Experiments were carried out on adult female Wistar rats. After isolation of muscle fibres from peroneus longus, influence of TNFα was tested on RP by using intracellular microelectrodes. Digoxin and chelerythrin were used to determine the mechanism of TNFα action. RESULTS: First, we found that TNFα induced a concentration dependent increase of muscle RP and that this mechanism, which was blocked by digoxin, was due to an effect on the Na/K ATPase. As it was also blocked by chelerythrin it was concluded that this effect was mediated by PKC activation of the Na/K ATPase. CONCLUSIONS: We demonstrated that TNFα leads to a PKC mediated increase in muscle RP. Depolarization needed to reach the threshold voltage for muscle action potential should then be higher and this could be involved in the decrease in muscle excitability observed in acquired polyneuromyopathy.

Tumor necrosis factor-α downregulates sodium current in skeletal muscle by protein kinase C activation: involvement in critical illness polyneuromyopathy.

Sepsis is involved in the decrease of membrane excitability of skeletal muscle, leading to polyneuromyopathy. This effect is mediated by alterations of the properties of voltage-gated sodium channels (Na(V)), but the exact mechanism is still unknown. The aim of the present study was to check whether tumor necrosis factor (TNF-α), a cytokine released during sepsis, exerts a rapid effect on Na(V). Sodium current (I(Na)) was recorded by macropatch clamp in skeletal muscle fibers isolated from rat peroneus longus muscle, in control conditions and after TNF-α addition. Analyses of dose-effect and time-effect relationships were carried out. Effect of chelerythrine, a PKC inhibitor, was also studied to determine the way of action of TNF-α. TNF-α induced a reversible dose- and time-dependent inhibition of I(Na). A maximum inhibition of 75% of the control current was observed. A shift toward more negative potentials of activation and inactivation curves of I(Na) was also noticed. These effects were prevented by chelerythrine pretreatment. TNF-α is a cytokine released in the early stages of sepsis. Besides a possible transcriptional role, i.e., modification of the channel type and/or number, we demonstrated the existence of a rapid, posttranscriptional inhibition of Na(V) by TNF-α. The downregulation of the sodium current could be mediated by a PKC-induced phosphorylation of the sodium channel, thus leading to a significant decrease in muscle excitability.

Na v1.4 and Na v1.5 are modulated differently during muscle immobilization and contractile phenotype conversion.

Muscle immobilization leads to modification in its fast/slow contractile phenotype. Since the properties of voltage-gated sodium channels (Na(v)) are different between "fast" and "slow" muscles, we studied the effects of immobilization on the contractile properties and the Na(v) of rat peroneus longus (PL). The distal tendon of PL was cut and fixed to the adjacent bone at neutral muscle length. After 4 or 8 wk of immobilization, the contractile and the Na(v) properties were studied and compared with muscles from control animals (Student's t-test). After 4 wk of immobilization, PL showed a faster phenotype with a rightward shift of the force-frequency curve and a decrease in both the Burke's index of fatigability and the tetanus-to-twitch ratio. These parameters showed opposite changes between 4 and 8 wk of immobilization. The maximal sodium current in 4-wk immobilized fibers was higher compared with that of control fibers (11.5 ± 1.2 vs. 7.8 ± 0.8 nA, P = 0.008), with partial recovery to the control values in 8-wk immobilized fibers (8.6 ± 0.7 nA, P = 0.48). In the presence of tetrodotoxin, the maximal residual sodium current decreased continuously throughout immobilization. Using the Western blot analysis, Na(v)1.4 expression showed a transient increase in 4-wk muscle, whereas Na(v)1.5 expression decreased during immobilization. Our results indicate that a muscle immobilized at optimal functional length with the preservation of neural inputs exhibits a transient fast phenotype conversion. Na(v)1.4 expression and current are related to the contractile phenotype variation.