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Background: The 3D printing technology allows to produce custom shapes and add functionalities to foot orthoses which offers better options for the treatment of flatfeet. This study aimed to assess the effect of 3D printed foot orthoses stiffness and/or a newly design posting on muscle activity, plantar pressures, and center of pressure displacement in individuals with flatfeet., Methods: Nineteen individuals with flatfeet took part in this study. Two pairs of foot orthoses with different stiffness were designed for each participant and 3D printed. In addition, the flexible foot orthoses could feature an innovative rearfoot posting. Muscle activity, plantar pressures, and center of pressure displacement were recorded during walking., Findings: Walking with foot orthoses did not alter muscle activity time histories. Regarding plantar pressures, the most notable changes were observed in the midfoot area, where peak pressures, mean pressures and contact area increased significantly during walking with foot orthoses. The latter was reinforced by increasing the stiffness. Concerning the center of pressure displacement, foot orthoses shifted the center of pressure forward and medially at early stance. At the end of the stance phase, a transition of the center of pressure in posterior direction was observed during the posting condition. No effect of stiffness was observed on center of pressure displacement., Interpretation: The foot orthoses stiffness and the addition of posting influenced plantar pressures during walking. The foot orthoses stiffness mainly altered the plantar pressures under the midfoot area. However, posting mainly acted on peak and mean pressures under the rearfoot area., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Individuals with pain report higher sensory disturbances during sensorimotor conflicts compared to pain-free individuals. In the pain field, it is frequently assumed that disturbances arise from a discordance between sensory and efference copies (defined as sensory-motor conflict), while in the sensorimotor control field they are considered to result from the incongruence between sensory modalities (defined as sensory-sensory conflict). The general aim of this study was to disentangle the relative contribution of motor efferences and sensory afferences to the increased sensitivity to sensorimotor conflicts in individual with fibromyalgia (n = 20) compared to controls (n = 20). We assessed sensory and motor disturbances during sensory-sensory and sensory-motor conflicts using a robotized exoskeleton interfaced with a 2D virtual environment. There was a significant interaction between the group and the type of conflict (p = 0.03). Moreover, the increase in conflict sensitivity from sensory-sensory to sensory-motor conflicts in fibromyalgia was related to conflict-induced motor disturbances (r = 0.57; p < 0.01), but did not result from a poorer proprioception (r = 0.12; p = 0.61). Therefore, it appears that higher conflict sensitivity in fibromyalgia is mainly explained by a sensory-motor conflict rather by a sensory-sensory conflict. We suggest this arises due to a deficit in updating predicted sensory feedback rather than in selecting appropriate motor commands., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic myeloproliferative neoplasms (MPN) are recognized as a cause of pulmonary hypertension (pH). We ought to describe the prevalence and characteristics of PH in a cohort of MPN who were screened using transthoracic echocardiography (TTE)., Methods: One hundred eighty-three newly diagnosed consecutive MPN patients were prospectively evaluated using TTE to detect PH., Results: Two patients were diagnosed with chronic eosinophilic leukemia, two patients had post-essential thrombocythemia (ET) myelofibrosis (MF), two patients had post-polycythemia vera (PV) MF, 11 patients had primary myelofibrosis (PMF), 28 patients had chronic myeloid leukemia (CML), 51 patients had PV, and 87 patients had ET. TTE was used to determine PH, and PH was suspected in 16 of 183 patients as follows: four with PV, seven with ET, two with PMF, and three with CML. Two patients with ET were excluded because of global cardiac failure. Three patients underwent right heart catheterization to confirm PH. The 14 (7.7%) patients with PH had no cardiac or lung disease that directly involved MPN in PH development., Conclusion: In this large cohort of 183 MPN patients, TTE was used to diagnose PH, and 14 patients (7.7%) developed PH. This prevalence was lower than expected based on previously reported data, but it remains higher than in the general population., (Copyright © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

The preclinical evaluation of nasally administered drug candidates requires screening studies based on in vitro models of the nasal mucosa. The aim of this study was to evaluate the morpho-functional characteristics of the 3D MucilAir™ nasal model with a pharmacological focus on [ATP]-binding cassette (ABC) efflux transporters. We initially performed a phenotypic characterization of the MucilAir™ model and assessed its barrier properties by immunofluorescence (IF), protein mass spectrometry and examination of histological sections. We then focused on the functional expression of the ABC transporters P-glycoprotein (P-gp), multidrug resistance associated protein (MRP)1, MRP2 and breast cancer resistance protein (BCRP) in bidirectional transport experiments. The MucilAir™ model comprises a tight, polarized, pseudo-stratified nasal epithelium composed of fully differentiated ciliated, goblet and basal cells. These ABC transporters were all expressed by the cell membranes. P-gp and BCRP were both functional and capable of actively effluxing substrates. The MucilAir™ model could consequently represent a potent tool for evaluating the interaction of nasally administered drugs with ABC transporters., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Many studies have described the dynamic modulation of corticospinal excitability of the prime movers during motor preparation. However although anticipatory postural adjustments (APA) are an inherent part of most voluntary movements, investigation of trunk muscle corticospinal excitability during motor preparation has been neglected in the literature. In the present study, the corticospinal excitability of the superficial multifidus (sMF) and rectus abdominis (RA) muscle has been assessed during the preparation of rapid arm flexions and extensions in fifteen participants. A Warning signal informed participants to prepare to move prior to a Go signal. Transcranial magnetic stimulation was applied during baseline and at 6 time intervals before (Delay period) or after (Motor execution period) the Go signal. Results revealed a significant inhibition of the amplitude of sMF motor-evoked potentials in both flexion and extension movements within the Delay period compared to baseline, while no significant modulation was observed for RA. During the Motor Execution period for arm extension, sMF displayed even more inhibition, along with a large and significant facilitation of RA. During the Motor execution period for arm flexion, sMF presented a trend toward larger motor-evoked potential amplitude compared to Delay period. These results suggest the existence of two concurrent mechanisms underlying motor preparation for APA: (i) before the Go signal, a nonspecific inhibitory mechanism for sMF, likely to preclude motor program release; (ii) after the Go signal, a task-specific modulation of corticospinal excitability consistent with the EMG pattern during the early phase of movement., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Pemetrexed is a systemic chemotherapeutic agent used in the treatment of malignant mesothelioma. This drug represents a potentially promising intraperitoneal (IP) agent to use for hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal mesothelioma. However, this has yet to be supported by preclinical studies. Therefore, we aimed to study the effect of pemetrexed dose and perfusion temperature on the resultant pemetrexed concentration in 3 different compartments (systemic circulation, portal circulation and peritoneal tissues) using a murine model., Methods: Under general anesthesia, 29 Sprague-Dawley rats were submitted to 3 different doses of IP pemetrexed (500, 1000 and 1500 mg/m 2 ) combined with 3 different perfusion temperatures (37, 40 and 43 °C) for a total duration of 25 min. At the end of perfusion, samples in different compartments (systemic circulation, portal circulation and peritoneum) were harvested and concentrations of pemetrexed were measured using high performance liquid chromatography., Results: With increasing dose of IP pemetrexed, higher concentrations were measured in the 3 compartments tested. In peritoneal cells, the difference between IP doses of 500 and 1000 mg/m 2 (2.03 vs. 19.17 μg/g, p < 0.001) was greater than the difference between 1000 and 1500 mg/m 2 (19.17 vs. 22.80 μg/g, p = 0.027). When the perfusion temperature increased, we observed a proportional rise of pemetrexed concentration in both the portal and systemic compartments; while in the peritoneal cells, the pemetrexed concentration increased up to 40 °C, after which it plateaued., Conclusion: Both heat and increasing doses of IP pemetrexed enhance peritoneal cell concentration of pemetrexed. However, for temperatures above 40 °C, pemetrexed concentration reached a plateau in peritoneal cells. Systemic and portal concentrations increased proportionally with both increasing temperatures and IP doses. We believe these results should be taken into consideration for the design of an eventual clinical study in humans., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

When subjects learn a novel motor task, several sources of feedback (proprioceptive, visual or auditory) contribute to the performance. Over the past few years, several studies have investigated the role of visual feedback in motor learning, yet evidence remains conflicting. The aim of this study was therefore to investigate the role of online visual feedback (VFb) on the acquisition and retention stages of motor learning associated with training in a reaching task. Thirty healthy subjects made ballistic reaching movements with their dominant arm toward two targets, on 2 consecutive days using a robotized exoskeleton (KINARM). They were randomly assigned to a group with (VFb) or without (NoVFb) VFb of index position during movement. On day 1, the task was performed before (baseline) and during the application of a velocity-dependent resistive force field (adaptation). To assess retention, participants repeated the task with the force field on day 2. Motor learning was characterized by: (1) the final endpoint error (movement accuracy) and (2) the initial angle (iANG) of deviation (motor planning). Even though both groups showed motor adaptation, the NoVFb-group exhibited slower learning and higher final endpoint error than the VFb-group. In some condition, subjects trained without visual feedback used more curved initial trajectories to anticipate for the perturbation. This observation suggests that learning to reach targets in a velocity-dependent resistive force field is possible even when feedback is limited. However, the absence of VFb leads to different strategies that were only apparent when reaching toward the most challenging target., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sensorimotor reorganization is believed to play an important role in the development and maintenance of phantom limb pain, but pain itself might modulate sensorimotor plasticity induced by deafferentation. Clinical and basic research support this idea, as pain prior to amputation increases the risk of developing post-amputation pain. The aim of this study was to examine the influence of experimental tonic cutaneous hand pain on the plasticity induced by temporary ischemic hand deafferentation. Sixteen healthy subjects participated in two experimental sessions (Pain, No Pain) in which transcranial magnetic stimulation was used to assess corticospinal excitability in two forearm muscles (flexor carpi radialis and flexor digitorum superficialis) before (T0, T10, T20, and T40) and after (T60 and T75) inflation of a cuff around the wrist. The cuff was inflated at T45 in both sessions and in the Pain session capsaicin cream was applied on the dorsum of the hand at T5. Corticospinal excitability was significantly greater during the Post-inflation phase (p=0.002) and increased similarly in both muscles (p=0.861). Importantly, the excitability increase in the Post-inflation phase was greater for the Pain than the No-Pain condition (p=0.006). Post-hoc analyses revealed a significant difference between the two conditions during the Post-inflation phase (p=0.030) but no difference during the Pre-inflation phase (p=0.601). In other words, the corticospinal facilitation was greater when pain was present prior to cuff inflation. These results indicate that pain can modulate the plasticity induced by another event, and could partially explain the sensorimotor reorganization often reported in chronic pain populations., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In Toxoplasma gondii, dense granules are known as the storage secretory organelles of the so-called GRA proteins (for dense granule proteins), which are destined to the parasitophorous vacuole (PV) and the PV-derived cyst wall. Recently, newly annotated GRA proteins targeted to the host cell nucleus have enlarged this view. Here we provide an update on the latest developments on the Toxoplasma secreted proteins, which to date have been mainly studied at both the tachyzoite and bradyzoite stages, and we point out that recent discoveries could open the issue of a possible, yet uncharacterized, distinct secretory pathway in Toxoplasma., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Converging evidence from animal and human studies has revealed that increased or decreased use of an extremity can lead to changes in cortical representation of the involved muscles. However, opposite experimental manipulations such as immobilization and motor training have sometimes been associated with similar cortical changes. Therefore, the behavioral relevance of these changes remains unclear. The purpose of this study was to observe the effect of the amount of use on hand muscle motor cortex representation by contrasting the effect of unspecific motor training and immobilization. Nine healthy volunteers were tested prior and after a 4-day exposure to two experimental conditions using a randomized cross-over design: a motor training condition (to play Guitar Hero 2h/day with the tested (nondominant) hand on the fret board) and an immobilization condition (to wear an immobilization splint 24h/day). Before and after each condition, motor cortex representation of the nondominant first dorsal interosseous (FDI) muscle was mapped using image-guided transcranial magnetic stimulation (TMS). At the behavioral level, results show that the training condition led to a 20% improvement in the trained task, while the immobilization condition resulted in a 36% decrease in the FDI maximal voluntary contraction. At the neurophysiological level, corticospinal excitability (e.g. Motor-evoked potential amplitude) was found to be decreased in response to immobilization, while no change was observed in response to motor training. No change was found for other TMS variables (motor thresholds or map location/volume/area) in either condition. In conclusion, our results indicate that a 4-day decrease, but not increase, in the amount of use of nondominant hand muscles is sufficient to induce a change in corticospinal excitability. The lack of a training effect might be explained by the use of an unspecific task (that is nevertheless representative of "real-life" training situations) and/or by insufficient duration/intensity to induce long-lasting changes., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

Action observation is increasingly considered as a rehabilitation tool as it can increase the cortical excitability of muscles involved in the observed movements and therefore produce effector-specific motor facilitation. In order to investigate the action observation mechanisms, simple single joint intransitive movements have commonly been used. Still, how the observation of everyday movements which often are the prime target of rehabilitation affects the observer cortical excitability remains unclear. Using transcranial magnetic stimulations, we aimed at verifying if the observation of everyday movements made by the proximal or distal upper-limb produces effector-specific motor facilitation in proximal (arm) and distal (hand) muscles of healthy subjects. Results suggest that, similar to simple intransitive movements, observation of more complex everyday movements involving mainly the proximal or distal part of upper limb induces different patterns of motor facilitation across upper limb muscles (P=0.02). However, we observed large inter-individual variability in the strength of the effector-specific motor facilitation induced by action observation. Yet, subjects had similar types of response (strong or weak effector-specific effects) when watching proximal or distal movements indicating that the facilitation pattern was highly consistent within subjects (r=0.83-0.88, P<0.001). This suggests that some individuals are better than other at precisely mapping the observed movements on their motor repertoire and that this type of response holds for various types of everyday actions., (Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

How eukaryotic pathogens export and sort membrane-bound proteins destined for host-cell compartments is still poorly understood. The dense granules of the intracellular protozoan Toxoplasma gondii constitute an unusual secretory pathway that allows soluble export of the GRA proteins which become membrane-associated within the parasite replicative vacuole. This process relies on both the segregation of the proteins routed to the dense granules from those destined to the parasite plasma membrane and on the sorting of the secreted GRA proteins to their proper final membranous system. Here, we provide evidence that the soluble trafficking of GRA6 to the dense granules relies on the N-terminal domain of the protein, which is sufficient to prevent GRA6 targeting to the parasite plasma membrane. We also show that the GRA6 N-terminal domain, possibly by interacting with negatively charged lipids, is fundamental for proper GRA6 association with the vacuolar membranous network of nanotubes. These results support our emerging model: sorting of transmembrane GRA proteins to the host cell vacuole is mainly driven by the dual role of their N-terminal hydrophilic domain and is compartmentally regulated., (Copyright (c) 2010. Published by Elsevier Ltd.)

Recent evidence shows that the primary motor cortex continues to send motor commands when amputees execute phantom movements. These commands are retargeted toward the remaining stump muscles as a result of motor system reorganization. As amputation-induced reorganization in the primary motor cortex has been associated with phantom limb pain we hypothesized that the motor control of the phantom limb would differ between amputees with and without phantom limb pain. Eight above-elbow amputees with or without pain were included in the study. They were asked to produce cyclic movements with their phantom limb (hand, wrist, and elbow movements) while simultaneously reproducing the same movement with the intact limb. The time needed to complete a movement cycle and its amplitude were derived from the kinematics of the intact limb. Electromyographic (EMG) activity from different stump muscles and from the homologous muscles on the intact side was recorded. Different EMG patterns were recorded in the stump muscles depending on the movement produced, showing that different phantom movements are associated with distinct motor commands. Phantom limb pain was associated with some aspects of phantom limb motor control. The time needed to complete a full cycle of a phantom movement was systematically shorter in subjects without phantom limb pain. Also, the amount of EMG modulation recorded in a stump muscle during a phantom hand movement was positively correlated with the intensity of phantom limb pain. Since phantom hand movement-related EMG patterns in above-elbow stump muscles can be considered as a marker of motor system reorganization, this result indirectly supports the hypothesis that amputation-induced plasticity is associated with phantom limb pain severity. The discordance between the (amputated) hand motor command and the feedback from above-elbow muscles might partially explain why subjects exhibiting large EMG modulation during phantom hand movement have more phantom limb pain.

The intracellular protozoan parasite Toxoplasma gondii develops within the parasitophorous vacuole (PV), an intracellular niche in which it secretes proteins from secretory organelles named dense granules and rhoptries. Here, we describe a new dense granule protein that should now be referred to as GRA12, and that displays no homology with other proteins. Immunofluorescence and immuno-electron microscopy showed that GRA12 behaves similarly to both GRA2 and GRA6. It is secreted into the PV from the anterior pole of the parasite soon after the beginning of invasion, transits to the posterior invaginated pocket of the parasite where a membranous tubulovesicular network is first assembled, and finally resides throughout the vacuolar space, associated with the mature membranous nanotubular network. GRA12 fails to localise at the parasite posterior end in the absence of GRA2. Within the vacuolar space, like the other GRA proteins, GRA12 exists in both a soluble and a membrane-associated form. Using affinity chromatography experiments, we showed that in both the parasite and the PV soluble fractions, GRA12 is purified with the complex of GRA proteins associated with a tagged version of GRA2 and that this association is lost in the PV membranous fraction.

Amphipathic alpha-helices have been proposed as the general means used by soluble proteins to induce membrane tubulation. Previous studies had shown that the GRA2 dense granule protein of Toxoplasma gondii would be a crucial protein for the formation of the intravacuolar membranous nanotubular network (MNN) and that one of the functions of the MNN is to organise the parasites within the parasitophorous vacuole. GRA2 is a small protein (185 amino acids), predicted to contain three amphipathic alpha-helices (alpha1: 70-92; alpha2: 95-110 and alpha3: 119-139) when using the standard programs of secondary structure prediction. To investigate the respective contribution of each alpha-helix in the GRA2 functions, we used DeltaGRA2-HXGPRT knock-out complementation: eight truncated forms of GRA2 were expressed in the deleted recipient and the phenotypes of these mutants were analysed. This study showed that: (i) alpha3, when associated with the N-terminal region (NT) and the C-terminal region (CT), is sufficient to target the protein to the parasite posterior end and to induce formation of membranous vesicles within the vacuole. However, when associated only with CT, alpha3 is not sufficient to provide the hydrophobicity required for membrane association; (ii) the alpha1alpha2 region is alone not sufficient to induce membrane tubulation within the PV; and (iii) only one mutant, NT-alpha1alpha2alpha3, restores most of the biochemical and functional properties of GRA2, including traffic to the dense granules, secretion into the vacuole, association with vacuolar membranes, induction of the MNN formation and organisation of the parasites within the vacuole.

To investigate the vaccine potential of both the Toxoplasma GRA2 and GRA6 antigens, the full length recombinant proteins were produced in Escherichia coli, formulated in MPL adjuvant, and used alone and in combination ("mix"), to immunize CBA/J mice. Although high ratios of specific IgG2a/IgG1 were measured against both proteins, only spleen cells from GRA2-immunized mice and mix-immunized mice produced high amounts of both IFN-gamma and IL-2 upon induction with Toxoplasma gondii Excretory-Secretory Antigens. Intra peritoneal challenge with Toxoplasma cysts resulted in significant reduction of brain cysts in GRA2- and in mix-vaccinated mice only. This study shows the protective efficacy of recombinant GRA2 against chronic infection by T. gondii and confirms the utility of MPL adjuvant in enabling a vaccine candidate to induce a protective Th1 immune response.

Together with micronemes and rhoptries, dense granules are specialised secretory organelles of Apicomplexa parasites. Among Apicomplexa, Plasmodium represents a model of parasites propagated by way of an insect vector, whereas Toxoplasma is a model of food borne protozoa forming cysts. Through comparison of both models, this review summarises data accumulated over recent years on alternative strategies chosen by these parasites to develop within a parasitophorous vacuole and explores the role of dense granules in this process. One of the characteristics of the Plasmodium erythrocyte stages is to export numerous parasite proteins into both the host cell cytoplasm and/or plasma membrane via the vacuole used as a step trafficking compartment. Whether this feature can be correlated to few storage granules and a restricted number of dense granule proteins, is not yet clear. By contrast, the Toxoplasma developing vacuole is decorated by abundantly expressed dense granule proteins and is characterised by a network of membranous nanotubes. Although the exact function of most of these proteins remains currently unknown, recent data suggest that some of these dense granule proteins could be involved in building the intravacuolar membranous network. Conserved expression of the Toxoplasma dense granule proteins throughout most of the parasite stages suggests that they could also be key elements of the cyst formation.

Important components of the parasitophorous vacuole in which the intracellular protozoan parasite Toxoplasma gondii develops, comprise proteins secreted from apicomplexan specific secretory organelles named the dense granules. Here, we confirm by immunofluorescence and by cryo-electron microscopy that the recently isolated B10 protein (318 amino acids, 41kDa) is a new dense granule protein that should now be referred to as GRA9. Within the vacuolar compartment, GRA9, like GRA2, GRA4 and GRA6, associates with the network of tubular membranes connected to the parasitophorous vacuole delimiting membrane. Like the other GRA proteins, GRA9 is secreted into the vacuole from the anterior end of the parasite. However, unlike GRA2 or GRA6, GRA9 does not transit by the posterior invaginated pocket of the parasite where the network first assembles. Within the dense granules, GRA9 exists in both a soluble and an insoluble state. Like the other GRA proteins, GRA9 is secreted as a soluble form only and like most of the GRA proteins, two forms of GRA9 of the similar molecular weight are detected within the vacuolar space: a soluble form and a membrane associated form. The dual properties of GRA9 are not only ascribed by the presence of amphipathic and hydrophobic alpha-helices but also by the fact that the protein is mainly hydrophilic.

Drug cerebral pharmacokinetics may be altered in the case of inflammatory diseases. This may be due to a modification of drug transport through the blood-brain barrier, in particular through drug interaction with the membrane efflux transporter, P-glycoprotein. The objective of this study was to investigate the influence of the inflammatory cytokine, tumor necrosis factor (TNF)-alpha, on the functionality and expression of P-glycoprotein, and on mdr1a and mdr1b mRNA expression in immortalised rat brain endothelial cells, GPNT. Cells were treated with TNF-alpha for 4 days. Levels of mdr1a and mdr1b mRNAs were quantitated using real-time RT-PCR analysis and expression of P-glycoprotein was analyzed by Western blot. The functionality of P-glycoprotein was studied by following the accumulation of [3H]vinblastine in the cells without and with a pre-treatment with a P-glycoprotein inhibitor, GF120918. TNF-alpha increased the levels of mdr1a and mdr1b mRNAs while no effect was observed on protein expression. TNF-alpha increased [3H]vinblastine accumulation indicating a time and concentration-dependent decrease of P-glycoprotein activity. This effect was eliminated when the cells were pre-treated with GF120918. Our observation of a decrease in P-glycoprotein activity could suggest that in the case of inflammatory diseases, brain delivery of P-glycoprotein-dependent drugs can be enhanced.

1. The fine structure of trout liver glycogen has been investigated using an enzymatic method. 2. The total conversion of glycogen into glucose under the action of amyloglucosidase and the percentage of beta-amylolysis before (37.4%) and after (97.8%) isoamylase debranching are similar to the mammalian glycogen. 3. However, the resistance to beta-amylase of certain debranched material leads to an hypothesis during glycogenolysis.

The activities of five enzymes have been studied quantitatively in denervated extensor digitorum longus, gastrocnemius and soleus muscles of 24-month-old rats. The results have been compared with those obtained from normal muscles of a similar age group of rats. Three weeks after denervation, the activity of hexokinase was increased in gastrocnemius and extensor digitorum longus. Phosphofructokinase, lactate dehydrogenase, malate dehydrogenase and 3-hydroxyacyl-CoA-dehydrogenase showed decreased activities. These results suggest that enzyme which represents glucose uptake increased its activity in fast muscles and that enzymes for anaerobic glycolysis, lactate fermentation, citric acid cycle and beta-oxidation had a decreased activity in slow and fast muscles.