Regulation of the akt signalling in human skeletal muscle atrophy

Abstract : The term "muscle disuse" is often used to refer collectively to reductions in neuromuscular activity as observed with sedentary lifestyles, reduced weight bearing, cancer, chronic obstructive pulmonary disease, chronic heart failure, spinal cord injury, sarcopenia or exposure to microgravity (spaceflight). Muscle disuse atrophy, caused by accelerated proteolysis, is predominantly due to the activation of the ATP-dependent ubiquitin (Ub) proteasome pathway. The current advances in understanding the molecular factors contributing to the Ub-dependent proteolysis process have been made mostly in rodent models of human disease and denervation with few investigations performed directly in humans. Recently, in mice, the genes Atrogin-1 and MuRF1 have been designated as primary candidates in the control of muscle atrophy. Additionally, the decreased activity of the Akt/GSK-3ß and Akt/mTOR pathways has been associated with a reduction in protein synthesis and contributing to skeletal muscle atrophy. Therefore, it is now commonly accepted that skeletal muscle atrophy is the result of a decreased protein synthesis concomitant with an increase in protein degradation (Glass 2003). Atrogin-1 and MuRF1 are genes expressed exclusively in muscle. In mice, their expression has been shown to be directly correlated with the severity of atrophy. KO-mice experiments showed a major protection against atrophy when either of these genes were deleted. Skeletal muscle hypertrophy is an important function in normal postnatal development and in the adaptive response to exercise. It has been shown, in vitro, that the activation of phosphatidylinositol 3-kinase (PI-3K), by insulin growth factor 1 (IGF-1), stimulates myotubes hypertrophy by activating the downstream pathways, Akt/GSK-3ß and Akt/mTOR. It has also been demonstrated in mice, in vivo, that activation of these signalling pathways causes muscle hypertrophy. Moreover, the latter were recently proposed to also reduce muscle atrophy by inhibiting the FKHR mediated transcription of several muscle atrophy genes; Atrogin-1 and MuRF1. Therefore, these targets present new avenues for developing further the understanding of the molecular mechanisms involved in both skeletal muscle atrophy and hypertrophy. The present study proposed to investigate the regulation of the Akt/GSK-3ß and Akt/mTOR signalling pathways, as well as the expression levels of the "atrogenes", Atrogin-1 and MuRF1, in four human models of skeletal muscle atrophy. In the first study, we measured the regulation of the Akt signalling pathway after 8 weeks of both hypertrophy stimulating resistance training and atrophy stimulation de-training. As expected following resistance training, muscle hypertrophy and an increase in the phosphorylation status of the different members of the Akt pathway was observed. This was paralleled by a concomitant decrease in FOXO1 nuclear protein content. Surprisingly, exercise training also induced an increase in the, expression of the atrophy genes and proteins involved in the ATP-dependant ubiquitin-proteasome system. On the opposite, following the de-training period a muscle atrophy, relative to the post-training muscle size, was measured. At the same time, the phosphorylation levels of Akt and GSK-3ß were reduced while the amount of FOXO1 in the nucleus increased. After the atrophy phase, there was also a reduction in Atrogin-1 and MuRF1 contents. In this study, we demonstrate for the first time in healthy human skeletal muscle, that the regulation of Akt and its downstream targets GSK-3ß, mTOR and FOXO1 are associated with both thé skeletal muscle hypertrophy and atrophy processes. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of both upper and lower motor neurons, which leads to severe muscle weakness and atrophy. All measurements were performed in biopsies from 22 ALS patients and 16 healthy controls. ALS patients displayed an increase in Atrogin-1 mRNA and protein content which was associated with a decrease in Akt activity. However there was no difference in the mRNA and phospho-protein content of FOXO1, FOXO3a, p70S6K and GSK-3ß. The transcriptional regulation of human Atrogin-1 may be controlled by an Akt-mediated transcription factor other than FKHR or via an other signalling pathway. Chronic complete spinal cord injury (SCI) is associated with severe muscle atrophy which is linked to co-morbidity factors such as diabetes, obesity, lipid disorders and cardiovascular diseases. Molecular mechanisms associated with chronic complete SCI-related muscle atrophy are not well understood. The aim of the present study was to determine if there was an increase in catabolic signalling targets such as Atrogin-1, MuRF1, FOXO and myostatin, and decreases in anabolic signalling targets such as IGF, Akt, GSK-3ß, mTOR, 4E-BP1 and p-70S6K in chronic complete SCI patients. All measurements were performed in biopsies taken from 8 complete chronic SCI patients and 7 age matched healthy controls. In SCI patients when compared with controls, there was a significant reduction in mRNA levels of Atrogin1, MuRF1 and Myostatin. Protein levels for Atrogin-1, FOX01 and FOX03a were also reduced. IGF-1 and both phosphorylated GSK-3ß and 4E-BP1 were decreased; the latter two in an Akt and mTOR independent manner, respectively. Reductions in Atrogin-1, MuRF1, FOXO and myostatin suggest the existence of an internal mechanism aimed at reducing further loss of muscle proteins during chronic SCI. The downregulation of signalling proteins regulating anabolism such as IGF, GSK3ß and 4E-BP1 would reduce the ability to increase protein synthesis rates in this chronic state of muscle wasting. The molecular mechanisms controlling age-related skeletal muscle loss in humans are poorly understood. The present study aimed to investigate the regulation of several genes and proteins involved in the activation of key signalling pathways promoting muscle hypertrophy such as GH/STAT5/IGF, IGF/Akt/GSK-3ß/4E-BP1 and muscle atrophy such as TNFα/SOCS3 and Akt/FOXO/Atrogin-1 or MuRF1 in muscle biopsies from 13 young and 16 elderly men. In the older, as compared with the young subjects, TNFα and SOCS-3 were increased while growth hormone receptor protein (GHR) and IGF-1 mRNA were both decreased. Akt protein levels were increased however no change in phosphorylated Akt content was observed. GSK-3ß phosphorylation levels were increased while 4E-BP1 was not changed. Nuclear FKHR and FKHRL1 protein levels were decreased, with no changes in their atrophy target genes, Atrogin-1 and MuRF1. Myostatin mRNA and protein levels were significantly elevated. Human sarcopenia may be linked to a reduction in the activity or sensitivity of anabolic signalling proteins such as GHR, IGF and Akt. TNFα, SOCS-3 and myostatin are potential candidates influencing this anabolic perturbation. In conclusion our results support those obtained in rodent or ín vitro models, and demonstrate Akt plays a pivotal role in the control of muscle mass in humans. However, the Akt phosphorylation status was dependant upon the model of muscle atrophy as Akt phosphorylation was reduced in all atrophy models except for SCI. Additionally, the activity pattern of the downstream targets of Akt appears to be different upon the various human models. It seems that under particular conditions such as spinal cord injury or sarcopenia, .the regulation of GSK-3ß, 4eBP1 and p70S6K might be independent of Akt suggesting alternative signalling pathways in the control of these the anabolic response in human skeletal muscle. The regulation of Atrogin-1 and MuRF1 in some of our studies has been shown to be also independent of the well-described Akt/FOXO signalling pathway suggesting that other transcription factors may regulate human Atrogin-1 and MuRF1. These four different models of skeletal muscle atrophy and hypertrophy have brought a better understanding concerning the molecular mechanisms controlling skeletal muscle mass in humans.

Effects of Intermittent Training on Anaerobic Performance and MCT Transporters in Athletes.

This study examined the effects of intermittent hypoxic training (IHT) on skeletal muscle monocarboxylate lactate transporter (MCT) expression and anaerobic performance in trained athletes. Cyclists were assigned to two interventions, either normoxic (N; n = 8; 150 mmHg PIO2) or hypoxic (H; n = 10; ∼3000 m, 100 mmHg PIO2) over a three week training (5×1 h-1h30.week-1) period. Prior to and after training, an incremental exercise test to exhaustion (EXT) was performed in normoxia together with a 2 min time trial (TT). Biopsy samples from the vastus lateralis were analyzed for MCT1 and MCT4 using immuno-blotting techniques. The peak power output (PPO) increased (p<0.05) after training (7.2% and 6.6% for N and H, respectively), but VO2max showed no significant change. The average power output in the TT improved significantly (7.3% and 6.4% for N and H, respectively). No differences were found in MCT1 and MCT4 protein content, before and after the training in either the N or H group. These results indicate there are no additional benefits of IHT when compared to similar normoxic training. Hence, the addition of the hypoxic stimulus on anaerobic performance or MCT expression after a three-week training period is ineffective.

Protein intake and exercise for optimal muscle function with aging: recommendations from the ESPEN Expert Group.

The aging process is associated with gradual and progressive loss of muscle mass along with lowered strength and physical endurance. This condition, sarcopenia, has been widely observed with aging in sedentary adults. Regular aerobic and resistance exercise programs have been shown to counteract most aspects of sarcopenia. In addition, good nutrition, especially adequate protein and energy intake, can help limit and treat age-related declines in muscle mass, strength, and functional abilities. Protein nutrition in combination with exercise is considered optimal for maintaining muscle function. With the goal of providing recommendations for health care professionals to help older adults sustain muscle strength and function into older age, the European Society for Clinical Nutrition and Metabolism (ESPEN) hosted a Workshop on Protein Requirements in the Elderly, held in Dubrovnik on November 24 and 25, 2013. Based on the evidence presented and discussed, the following recommendations are made (a) for healthy older people, the diet should provide at least 1.0-1.2 g protein/kg body weight/day, (b) for older people who are malnourished or at risk of malnutrition because they have acute or chronic illness, the diet should provide 1.2-1.5 g protein/kg body weight/day, with even higher intake for individuals with severe illness or injury, and (c) daily physical activity or exercise (resistance training, aerobic exercise) should be undertaken by all older people, for as long as possible.

Addition of inspiratory resistance increases the amplitude of the slow component of O2 uptake kinetics.

The contribution of respiratory muscle work to the development of the O(2) consumption (Vo(2)) slow component is a point of controversy because it has been shown that the increased ventilation in hypoxia is not associated with a concomitant increase in Vo(2) slow component. The first purpose of this study was thus to test the hypothesis of a direct relationship between respiratory muscle work and Vo(2) slow component by manipulating inspiratory resistance. Because the conditions for a Vo(2) slow component specific to respiratory muscle can be reached during intense exercise, the second purpose was to determine whether respiratory muscles behave like limb muscles during heavy exercise. Ten trained subjects performed two 8-min constant-load heavy cycling exercises with and without a threshold valve in random order. Vo(2) was measured breath by breath by using a fast gas exchange analyzer, and the Vo(2) response was modeled after removal of the cardiodynamic phase by using two monoexponential functions. As anticipated, when total work was slightly increased with loaded inspiratory resistance, slight increases in base Vo(2), the primary phase amplitude, and peak Vo(2) were noted (14.2%, P < 0.01; 3.5%, P > 0.05; and 8.3%, P < 0.01, respectively). The bootstrap method revealed small coefficients of variation for the model parameter, including the slow-component amplitude and delay (15 and 19%, respectively), indicating an accurate determination for this critical parameter. The amplitude of the Vo(2) slow component displayed a 27% increase from 8.1 +/- 3.6 to 10.3 +/- 3.4 ml. min(-1). kg(-1) (P < 0.01) with the addition of inspiratory resistance. Taken together, this increase and the lack of any differences in minute volume and ventilatory parameters between the two experimental conditions suggest the occurrence of a Vo(2) slow component specific to the respiratory muscles in loaded condition.

Significant molecular and systemic adaptations after repeated sprint training in hypoxia

While intermittent hypoxic training (IHT) has been reported to evoke cellular responses via hypoxia inducible factors (HIFs) but without substantial performance benefits in endurance athletes, we hypothesized that repeated sprint training in hypoxia could enhance repeated sprint ability (RSA) performed in normoxia via improved glycolysis and O(2) utilization. 40 trained subjects completed 8 cycling repeated sprint sessions in hypoxia (RSH, 3000 m) or normoxia (RSN, 485 m). Before (Pre-) and after (Post-) training, muscular levels of selected mRNAs were analyzed from resting muscle biopsies and RSA tested until exhaustion (10-s sprint, work-to-rest ratio 1ratio2) with muscle perfusion assessed by near-infrared spectroscopy. From Pre- to Post-, the average power output of all sprints in RSA was increased (p<0.01) to the same extent (6% vs 7%, NS) in RSH and in RSN but the number of sprints to exhaustion was increased in RSH (9.4+/-4.8 vs. 13.0+/-6.2 sprints, p<0.01) but not in RSN (9.3+/-4.2 vs. 8.9+/-3.5). mRNA concentrations of HIF-1alpha (+55%), carbonic anhydrase III (+35%) and monocarboxylate transporter-4 (+20%) were augmented (p<0.05) whereas mitochondrial transcription factor A (-40%), peroxisome proliferator-activated receptor gamma coactivator 1alpha (-23%) and monocarboxylate transporter-1 (-36%) were decreased (p<0.01) in RSH only. Besides, the changes in total hemoglobin variations (Delta[tHb]) during sprints throughout RSA test increased to a greater extent (p<0.01) in RSH. Our findings show larger improvement in repeated sprint performance in RSH than in RSN with significant molecular adaptations and larger blood perfusion variations in active muscles.

A new paradigm of neuromuscular electrical stimulation for the quadriceps femoris muscle.

PURPOSE: Neuromuscular electrical stimulation (NMES) with large electrodes and multiple current pathways (m-NMES) has recently been proposed as a valid alternative to conventional NMES (c-NMES) for quadriceps muscle (re)training. The main aim of this study was to compare discomfort, evoked force and fatigue between m-NMES and c-NMES of the quadriceps femoris muscle in healthy subjects. METHODS: Ten healthy subjects completed two experimental sessions (c-NMES and m-NMES), that were randomly presented in a cross-over design. Maximal electrically evoked force at pain threshold, self-reported discomfort at different levels of evoked force, and fatigue-induced force declines during and following a series of 20 NMES contractions were compared between c-NMES and m-NMES. RESULTS: m-NMES resulted in greater evoked force (P < 0.05) and lower discomfort in comparison to c-NMES (P < 0.05-0.001), but fatigue time course and magnitude did not differ between the two conditions. CONCLUSIONS: The use of quadriceps m-NMES appears legitimate for (re)training purposes because it generated stronger contractions and was less discomfortable than c-NMES (due to multiple current pathways and/or lower current density with larger electrodes).

Whole-Body Vibration Training Elevates Creatine-Kinase Levels in Sedentary Subjects

METHODS: 20 inactive (10 male, 10 female) underwent a single typical WBV session, with a total of 27 minutes of exercise on an oscillating platform at 26 Hz, involving upper and lower body muscles. Each exercise lasted 90 seconds, with 40 seconds pauses inbetween. Muscle enzymes (CK, transaminase, LDH, troponin I) were measured before, at 24, 48 and 96 hours post exercise. Lactate was measured immediately after the session. Muscle aches were assessed during 4 days post-exercise.RESULTS: Subjects' mean age was 23.0 ± 3.5 (male), 22.4 ± 1.4 (female), BMI 22.8 ± 2.3 and 22.1 ± 1.9, and all had been inactive for at least 12 months. Post exercise lactatemia was 10.0 ± 2.4 and 6.9 ± 2.4. CK elevation was significant (at least doubling of baseline values) in 1 male and 4 female subjects, while they remained at baseline values for the remaining 15 subjects. One female subject peaked at 3520 U/l at 96 hours post exercise, and all but one peaked at the same late time. Troponin and CK-MB never increased. No correlation was found between muscle soreness and CK levels.CONCLUSIONS: WBV can elicit important anaerobic processes reflected by the high lactacidemia, and CK elevation was significant in 25 % of subjects, peaking at the fourth day after exercise for 80 % of those. Such exercises should not be regarded as trivial and "easy" as they are advertised, since they can provoke important anaerobia and CK elevation. Many fragile patients or patients treated for cardiovascular disease could benefit from WBV but it is important to recognise these potential effects, especially in those treated with statins, known to cause a myopathy and CK elevation. Before considering a side effect of an important therapeutic agent, doctors should be aware of the possible interaction with not-so-harmless exercising machines.

Increasing lactate turnover rate during exercise by means of altitude training and fructose ingestion : effects on substrate metabolism and endurance performance

Summary : With regard to exercise metabolism, lactate was long considered as a dead-end waste product responsible for muscle fatigue and a limiting factor for motor performance. However, a large body of evidence clearly indicates that lactate is an energy efficient metabolite able to link the glycolytic pathway with aerobic metabolism and has endocrine-like actions, rather than to be a dead-end waste product. Lactate metabolism is also known to be quickly upregulated by regular endurance training and is thought to be related to exercise performance. However, to what extent its modulation can increase exercise performance in already endurance-trained subjects is unknown. The general hypothesis of this work was therefore that increasing either lactate metabolic clearance rate or lactate availability could, in turn, increase endurance performance. The first study (Study I) aimed at increasing the lactate clearance rate by means of assumed interaction effects of endurance training and hypoxia on lactate metabolism and endurance performance. Although this study did not demonstrate any interaction of training and hypoxia on both lactate metabolism and endurance performance, a significant deleterious effect of endurance training in hypoxia was shown on glucose homeostasis. The methods used to determine lactate kinetics during exercise exhibited some limitations, and the second study did delineate some of the issues raised (Study 2). The third study (Study 3) investigated the metabolic and performance effects of increasing plasma lactate production and availability during prolonged exercise in the fed state. A nutritional intervention was used for this purpose: part of glucose feedings ingested during the control condition was substituted by fructose. The results of this study showed a significant increase of lactate turnover rate, quantified the metabolic fate of fructose; and demonstrated a significant decrease of lipid oxidation and glycogen breakdown. In contrast, endurance performance appeared to be unmodified by this dietary intervention, being at odds with recent reports. Altogether the results of this thesis suggest that in endurance athletes the relationship between endurance performance and lactate turnover rate remains unclear. Nonetheless, the result of the present study raises questions and opens perspectives on the rationale of using hypoxia as a therapeutic aid for the treatment of insulin resistance. Moreover, the results of the second study open perspectives on the role of lactate as an intermediate metabolite and its modulatory effects on substrate metabolism during exercise. Additionally it is suggested that the simple nutritional intervention used in the third study can be of interest in the investigation on the aforementioned roles of lactate. Résumé : Lorsque le lactate est évoqué en rapport avec l'exercice, il est souvent considéré comme un déchet métabolique responsable de l'acidose métabolique, de la fatigue musculaire ou encore comme un facteur limitant de la performance. Or la littérature montre clairement que le lactate se révèle être plutôt un métabolite utilisé efficacement par de nombreux tissus par les voies oxydatives et, ainsi, il peut être considéré comme un lien entre le métabolisme glycolytique et le métabolisme oxydatif. De plus on lui prête des propriétés endocrines. Il est connu que l'entraînement d'endurance accroît rapidement le métabolisme du lactate, et il est suggéré que la performance d'endurance est liée à son métabolisme. Toutefois la relation entre le taux de renouvellement du lactate et la performance d'endurance est peu claire, et, de même, de quelle manière la modulation de son métabolisme peut influencer cette dernière. Le but de cette thèse était en conséquence d'investiguer de quelle manière et à quel degré l'augmentation du métabolisme du lactate, par l'augmentation de sa clearance et de son turnover, pouvait à son tour améliorer la performance d'endurance de sujets entraînés. L'objectif de la première étude a été d'augmenter la clearance du lactate par le biais d'un entraînement en conditions hypoxiques chez des cyclistes d'endurance. Basé sur la littérature scientifique existante, on a fait l'hypothèse que l'entraînement d'endurance et l'hypoxie exerceraient un effet synergétique sur le métabolisme du lactate et sur la performance, ce qui permettrait de montrer des relations entre performance et métabolisme du lactate. Les résultats de cette étude n'ont montré aucun effet synergique sur la performance ou le métabolisme du lactate. Toutefois, un effet délétère sur le métabolisme du glucose a été démontré. Quelques limitations de la méthode employée pour la mesure du métabolisme du lactate ont été soulevées, et partiellement résolues dans la seconde étude de ce travail, qui avait pour but d'évaluer la sensibilité du modèle pharmacodynamique utilisé pour le calcul du turnover du lactate. La troisième étude a investigué l'effet d'une augmentation de la lactatémie sur le métabolisme des substrats et sur la performance par une intervention nutritionnelle substituant une partie de glucose ingéré pendant l'exercice par du fructose. Les résultats montrent que les composants dynamiques du métabolisme du lactate sont significativement augmentés en présence de fructose, et que les oxydations de graisse et de glycogène sont significativement diminuées. Toutefois aucun effet sur la performance n'a été démontré. Les résultats de ces études montrent que la relation entre le métabolisme du lactate et la performance reste peu claire. Les résultats délétères de la première étude laissent envisager des pistes de travail, étant donné que l'entraînement en hypoxie est considéré comme outil thérapeutique dans le traitement de pathologies liées à la résistance à l'insuline. De plus les résultats de la troisième étude ouvrent des perspectives de travail quant au rôle du lactate comme intermédiaire métabolique durant l'exercice ainsi que sur ses effets directs sur le métabolisme. Ils suggèrent de plus que la manipulation nutritionnelle simple qui a été utilisée se révèle être un outil prometteur dans l'étude des rôles et effets métaboliques que peut revêtir le lactate durant l'exercice.

Cellular distribution of Hsp70 expression in rat skeletal muscles. Effects of moderate exercise training and chronic hypoxia.

Rat hindlimb muscles constitutively express the inducible heat shock protein 72 (Hsp70), apparently in proportion to the slow myosin content. Since it remains controversial whether chronic Hsp70 expression reflects the overimposed stress, we investigated Hsp70 cellular distribution in fast muscles of the posterior rat hindlimb after (1) mild exercise training (up to 30 m/min treadmill run for 1 h/day), which induces a remodeling in fast fiber composition, or (2) prolonged exposure to normobaric hypoxia (10%O(2)), which does not affect fiber-type composition. Both conditions increased significantly protein Hsp70 levels in the skeletal muscle. Immunohistochemistry showed the labeling for Hsp70 in subsets of both slow/type 1 and fast/type 2A myofibers of control, sedentary, and normoxic rats. Endurance training increased about threefold the percentage of Hsp70-positive myofibers (P < 0.001), and changed the distribution of Hsp70 immunoreactivity, which involved a larger subset of both type 2A and intermediate type 2A/2X myofibers (P < 0.001) and vascular smooth muscle cells. Hypoxia induced Hsp70 immunoreactivity in smooth muscle cells of veins and did not increase the percentage of Hsp70-positive myofibers; however, sustained exposure to hypoxia affected the distribution of Hsp70 immunoreactivity, which appeared detectable in a very small subset of type 2A fibers, whereas it concentrated in type 1 myofibers (P < 0.05) together with the labeling for heme-oxygenase isoform 1, a marker of oxidative stress. Therefore, the chronic induction of Hsp70 expression in rat skeletal muscles is not obligatory related to the slow fiber phenotype but reveals the occurrence of a stress response.

Chronic low-frequency rTMS of primary motor cortex diminishes exercise training-induced gains in maximal voluntary force in humans.

Although there is consensus that the central nervous system mediates the increases in maximal voluntary force (maximal voluntary contraction, MVC) produced by resistance exercise, the involvement of the primary motor cortex (M1) in these processes remains controversial. We hypothesized that 1-Hz repetitive transcranial magnetic stimulation (rTMS) of M1 during resistance training would diminish strength gains. Forty subjects were divided equally into five groups. Subjects voluntarily (Vol) abducted the first dorsal interosseus (FDI) (5 bouts x 10 repetitions, 10 sessions, 4 wk) at 70-80% MVC. Another group also exercised but in the 1-min-long interbout rest intervals they received rTMS [Vol+rTMS, 1 Hz, FDI motor area, 300 pulses/session, 120% of the resting motor threshold (rMT)]. The third group also exercised and received sham rTMS (Vol+Sham). The fourth group received only rTMS (rTMS_only). The 37.5% and 33.3% gains in MVC in Vol and Vol+Sham groups, respectively, were greater (P = 0.001) than the 18.9% gain in Vol+rTMS, 1.9% in rTMS_only, and 2.6% in unexercised control subjects who received no stimulation. Acutely, within sessions 5 and 10, single-pulse TMS revealed that motor-evoked potential size and recruitment curve slopes were reduced in Vol+rTMS and rTMS_only groups and accumulated to chronic reductions by session 10. There were no changes in rMT, maximum compound action potential amplitude (M(max)), and peripherally evoked twitch forces in the trained FDI and the untrained abductor digiti minimi. Although contributions from spinal sources cannot be excluded, the data suggest that M1 may play a role in mediating neural adaptations to strength training.

Maximal lipid oxidation during exercise: a target for individualizing endurance training in obesity and diabetes?

This review summarizes the rationale for personalized exercise training in obesity and diabetes, targeted at the level of maximal lipid oxidation as can be determined by exercise calorimetry. This measurement is reproducible and reflects muscles' ability to oxidize lipids. Targeted training at this level is well tolerated, increases the ability to oxidize lipids during exercise and improves body composition, lipid and inflammatory status, and glycated hemoglobin, thus representing a possible future strategy for exercise prescription in patients suffering from obesity and diabetes.

Volitional assessment of respiratory muscle strength.

Respiratory muscle weakness may induce dyspnoea, secretion retention and respiratory failure. Assessing respiratory muscle strength is mandatory in neuromuscular diseases and in case of unexplained dyspnoea. A step by step approach is recommended, starting with simple volitional tests. Using spirometry, respiratory muscle weakness may be suspected on the basis of an abnormal flow-volume loop or a fall of supine vital capacity. When normal, maximal inspiratory and expiratory pressures against a near complete occlusion exclude significant muscle weakness, but low values are more difficult to interpret. Sniff nasal inspiratory pressure is a useful alternative because it is easy and it eliminates the problem of air leaks around the mouthpiece in patients with neuromuscular disorders. The strength available for coughing is easily assessed by measuring peak cough flow. In most cases, these simple non invasive tests are sufficient to confirm or to eliminate significant respiratory muscle weakness and help the timely introduction of ventilatory support or assisted cough techniques. In a minority of patients, a more complete evaluation is necessary using non volitional tests like cervical magnetic stimulation of phrenic nerves.

Closed loop electrical muscle stimulation in spinal cord injured rehabilitation

The effect of motor training using closed loop controlled Functional Electrical Stimulation (FES) on motor performance was studied in 5 spinal cord injured (SCI) volunteers. The subjects trained 2 to 3 times a week during 2 months on a newly developed rehabilitation robot (MotionMaker?). The FES induced muscle force could be adequately adjusted throughout the programmed exercises by the way of a closed loop control of the stimulation currents. The software of the MotionMaker? allowed spasms to be detected accurately and managed in a way to prevent any harm to the SCI persons. Subjects with incomplete SCI reported an increased proprioceptive awareness for motion and were able to achieve a better voluntary activation of their leg muscles during controlled FES. At the end of the training, the voluntary force of the 4 incomplete SCI patients was found increased by 388% on their most affected leg and by 193% on the other leg. Active mobilisation with controlled FES seems to be effective in improving motor function in SCI persons by increasing the sensory input to neuronal circuits involved in motor control as well as by increasing muscle strength.

Akt signalling through GSK-3beta, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy

Skeletal muscle size is tightly regulated by the synergy between anabolic and catabolic signalling pathways which, in humans, have not been well characterized. Akt has been suggested to play a pivotal role in the regulation of skeletal muscle hypertrophy and atrophy in rodents and cells. Here we measured the amount of phospho-Akt and several of its downstream anabolic targets (glycogen synthase kinase-3beta (GSK-3beta), mTOR, p70(s6k) and 4E-BP1) and catabolic targets (Foxo1, Foxo3, atrogin-1 and MuRF1). All measurements were performed in human quadriceps muscle biopsies taken after 8 weeks of both hypertrophy-stimulating resistance training and atrophy-stimulating de-training. Following resistance training a muscle hypertrophy ( approximately 10%) and an increase in phospho-Akt, phospho-GSK-3beta and phospho-mTOR protein content were observed. This was paralleled by a decrease in Foxo1 nuclear protein content. Following the de-training period a muscle atrophy (5%), relative to the post-training muscle size, a decrease in phospho-Akt and GSK-3beta and an increase in Foxo1 were observed. Atrogin-1 and MuRF1 increased after the hypertrophy and decreased after the atrophy phases. We demonstrate, for the first time in human skeletal muscle, that the regulation of Akt and its downstream signalling pathways GSK-3beta, mTOR and Foxo1 are associated with both the skeletal muscle hypertrophy and atrophy processes

A systems biology approach identifies molecular networks defining skeletal muscle abnormalities in chronic obstructive pulmonary disease.

Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory process of the lung inducing persistent airflow limitation. Extensive systemic effects, such as skeletal muscle dysfunction, often characterize these patients and severely limit life expectancy. Despite considerable research efforts, the molecular basis of muscle degeneration in COPD is still a matter of intense debate. In this study, we have applied a network biology approach to model the relationship between muscle molecular and physiological response to training and systemic inflammatory mediators. Our model shows that failure to co- ordinately activate expression of several tissue remodelling and bioenergetics pathways is a specific landmark of COPD diseased muscles. Our findings also suggest that this phenomenon may be linked to an abnormal expression of a number of histone modifiers, which we discovered correlate with oxygen utilization. These observations raised the interesting possibility that cell hypoxia may be a key factor driving skeletal muscle degeneration in COPD patients.