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The geological analysis of the Albanian-Macedonian transect constraints a framework of the Internal Hellenides in which 3 or 4 Jurassic oceanic basins opened at 174–160 Ma; they bordered the Western European Continent. During the Late Jurassic, the oceanic crusts subducted eastward, the Mirdita basin below the Pelagonian continent, the Almopias basin below the Malarupa-Veles continent and the Thessaloniki ophiolitic basin below the Continental Margin of the basin. A Paikon Volcanic tholeiitic Island Arc formed above the Almopias subduction and subsequently subducted below the rhyolitic volcanic centre of the Arc; the Guevgueli ophiolitic back-arc basin opened above the subduction of the Paikon Volcanic Arc (164–160 Ma). The top-to-the-W Late Jurassic obduction of the oceanic crusts (D 1 event) is followed by a gravitational exhumation (D 2 event). A new Mid-Late Cretaceous Almopias marine basin formed; the Late Cretaceous-Palaeocene continental subduction (=collisions, D 3-4 events) re-activated the Jurassic subductions and a dacitic Paikon Volcanic Arc formed in the Palaeocene-Early Eocene (56–45 Ma). The Vardar Trough opened at 45 Ma in the back of the dacitic Paikon Volcanic Arc, above the subduction of Vardar and Apulia units; it was submitted in the Late Priabonian to a tectonic event (D 5 event, 36–34 Ma) and to the Early Miocene compression (D 6 event). The N. Aegean WNW-ESE extension began at ∼21–20 Ma; change from the WNW to the NE-SW/N-S extensional directions occurred between the Tortonian (∼12 Ma) and the Pliocene (∼6 Ma); it was probably driven by hundreds kms of NE-SW/N-S stretching of the Central and Southern Aegean basins. L’analyse géologique du transect Albanie-Macédoine contraint une architecture des Hellénides Internes avec 3 ou 4 bassins océaniques jurassiques qui s’ouvrent à ∼174–160 Ma et bordent le continent de l’Europe occidentale. Ces basins subductent vers l’est au cours du Jurassique Supérieur, le bassin de Mirdita sous le continent Pélagonien, celui d’Almopias sous le continent de Malarupa-Veles et celui de Thessalonique sous la marge continentale orientale du bassin E. Peonias. Le centre volcanique tholeiitique (island-arc) du Paikon, se forme au-dessus de la subduction d’Almopias et subducte ensuite sous le centre volcanique rhyolitique de l’Arc. Le bassin ophiolitique d’arrière-arc de Guevgueli se forme au-dessus de la subduction de l’Arc à 164–160 Ma. L’obduction vers l’ouest des croûtes océaniques (événement D 1 ) est suivie par leur exhumation gravitationnelle (événement D 2 ) et un nouveau bassin marin d’Almopias se forme au Crétacé Moyen-Supérieur. Des subductions continentales (=collisions, évènements D 3-4 ) réactivent les subductions jurassiques et un Arc dacitique-andésitique du Paikon se forme au-dessus de la subduction continentale d’Almopias au Paléocène-Eocène inférieur. Le basin molassique du Vardar s’ouvre à 45 Ma à l’arrière de l’Arc dacitique du Paikon au-dessus de la subduction des unités vardariennes et apuliennes ; il est plissé au Priabonien supérieur (évènement D 5 , 36–34 Ma). La compression du Miocène inférieur (évènement D 6 , ∼20–20,5 Ma) est suivie en Egée du Nord par une extension WNW-ESE (∼21–20 Ma) qui devient NE-SW/N-S entre le Tortonien et le Pliocène (∼12–6 Ma) ; ce changement est probablement la conséquence de l’étirement NE-SW/N-S de plusieurs centaines de kms des bassins Centre et Sud Egéens.

Oxidative stress is thought to be one of the most important mechanisms implicated in the muscle wasting of chronic obstructive pulmonary disease (COPD) patients, but its role has never been demonstrated. We therefore assessed the effects of both pro-oxidant and antioxidant treatments on the oxidative stress levels and atrophic signaling pathway of cultured COPD myotubes. Treatment of cultured COPD myotubes with the pro-oxidant molecule H2O2 resulted in increased ROS production (P = 0.002) and protein carbonylation (P = 0.050), in association with a more pronounced atrophy of the myotubes, as reflected by a reduced diameter (P = 0.003), and the activated expression of atrophic markers MuRF1 and FoxO1 (P = 0.022 and P = 0.030, respectively). Conversely, the antioxidant molecule ascorbic acid induced a reduction in ROS production (P<0.001) and protein carbonylation (P = 0.019), and an increase in the myotube diameter (P<0.001) to a level similar to the diameter of healthy subject myotubes, in association with decreased expression levels of MuRF1, atrogin-1 and FoxO1 (P<0.001, P = 0.002 and P = 0.042, respectively). A significant negative correlation was observed between the variations in myotube diameter and the variations in the expression of MuRF1 after antioxidant treatment (P = 0.047). Moreover, ascorbic acid was able to prevent the H2O2-induced atrophy of COPD myotubes. Last, the proteasome inhibitor MG132 restored the basal atrophy level of the COPD myotubes and also suppressed the H2O2-induced myotube atrophy. These findings demonstrate for the first time the involvement of oxidative stress in the atrophy of COPD peripheral muscle cells in vitro, via the FoxO1/MuRF1/atrogin-1 signaling pathway of the ubiquitin/proteasome system.

Diaphragmatic function is a major determinant of the ability to successfully wean patients from mechanical ventilation (MV). Paradoxically, MV itself results in a rapid loss of diaphragmatic strength in animals. However, very little is known about the time course or mechanistic basis for such a phenomenon in humans. To determine in a prospective fashion the time course for development of diaphragmatic weakness during MV; and the relationship between MV duration and diaphragmatic injury or atrophy, and the status of candidate cellular pathways implicated in these phenomena. Airway occlusion pressure (TwPtr) generated by the diaphragm during phrenic nerve stimulation was measured in short-term (0.5 h; n = 6) and long-term (>5 d; n = 6) MV groups. Diaphragmatic biopsies obtained during thoracic surgery (MV for 2-3 h; n = 10) and from brain-dead organ donors (MV for 24-249 h; n = 15) were analyzed for ultrastructural injury, atrophy, and expression of proteolysis-related proteins (ubiquitin, nuclear factor-κB, and calpains). TwPtr decreased progressively during MV, with a mean reduction of 32 ± 6% after 6 days. Longer periods of MV were associated with significantly greater ultrastructural fiber injury (26.2 ± 4.8 vs. 4.7 ± 0.6% area), decreased cross-sectional area of muscle fibers (1,904 ± 220 vs. 3,100 ± 329 μm²), an increase of ubiquitinated proteins (+19%), higher expression of p65 nuclear factor-κB (+77%), and greater levels of the calcium-activated proteases calpain-1, -2, and -3 (+104%, +432%, and +266%, respectively) in the diaphragm. Diaphragmatic weakness, injury, and atrophy occur rapidly in critically ill patients during MV, and are significantly correlated with the duration of ventilator support.

The fixation of unstable zygomaticomaxillary complex (ZMC) fractures can be achieved by open reduction with rigid internal fixation (ORIF) and/or by closed reduction with percutaneous transfacial Kirschner wire fixation (CRWF). The aim of this study was to tomographically assess the symmetry and the protrusion of the cheekbone with unstable ZMC fractures that had been treated by ORIF vs. CRWF. Sixty patients exhibiting a surgically unstable tetrapodal ZMC fracture were included in this multicenter retrospective study. The coordinates of 5 landmarks representing the zygomatic protrusion were comparatively studied on the healthy and on the broken side using preoperative and postoperative tridimensional computed tomography (CT) scans or cone beam CT. No significant difference was found in the zygomatic protrusion irrespective of the surgical technique that was used. The zygomatico-maxillary ansa was found to be the most complicated area to reduce, particularly in the frontal plane with both the CRWF and the ORIF technique (p1 = 0.001 and p2 = 0.0009, respectively). There was no difference in terms of the level of complications, while the mean duration of the surgery was significantly less for the CRWF group. With good postoperative radiographic outcomes, the CRWF can be proposed as an alternative or in association with the ORIF technique for fixation of tetrapodal fractures of the ZMC.

To assess the clinical efficacy of nutritional amounts of grape polyphenols (PPs) in counteracting the metabolic alterations of high-fructose diet, including oxidative stress and insulin resistance (IR), in healthy volunteers with high metabolic risk. Thirty-eight healthy overweight/obese first-degree relatives of type 2 diabetic patients (18 men and 20 women) were randomized in a double-blind controlled trial between a grape PP (2 g/day) and a placebo (PCB) group. Subjects were investigated at baseline and after 8 and 9 weeks of supplementation, the last 6 days of which they all received 3 g/kg fat-free mass/day of fructose. The primary end point was the protective effect of grape PPs on fructose-induced IR. In the PCB group, fructose induced 1) a 20% decrease in hepatic insulin sensitivity index (P < 0.05) and an 11% decrease in glucose infusion rate (P < 0.05) as evaluated during a two-step hyperinsulinemic-euglycemic clamp, 2) an increase in systemic (urinary F2-isoprostanes) and muscle (thiobarbituric acid-reactive substances and protein carbonylation) oxidative stress (P < 0.05), and 3) a downregulation of mitochondrial genes and decreased mitochondrial respiration (P < 0.05). All the deleterious effects of fructose were fully blunted by grape PP supplementation. Antioxidative defenses, inflammatory markers, and main adipokines were affected neither by fructose nor by grape PPs. A natural mixture of grape PPs at nutritional doses efficiently prevents fructose-induced oxidative stress and IR. The current interest in grape PP ingredients and products by the global food and nutrition industries could well make them a stepping-stone of preventive nutrition.

Muscle satellite cells are resistant to cytotoxic agents, and they express several genes that confer resistance to stress, thus allowing efficient dystrophic muscle regeneration after transplantation. However, once they are activated, this capacity to resist to aggressive agents is diminished resulting in massive death of transplanted cells. Although cell immaturity represents a survival advantage, the signalling pathways involved in the control of the immature state remain to be explored. Here, we show that incubation of human myoblasts with retinoic acid impairs skeletal muscle differentiation through activation of the retinoic-acid receptor family of nuclear receptor. Conversely, pharmacologic or genetic inactivation of endogenous retinoic-acid receptors improved myoblast differentiation. Retinoic acid inhibits the expression of early and late muscle differentiation markers and enhances the expression of myogenic specification genes, such as PAX7 and PAX3 . These results suggest that the retinoic-acid-signalling pathway might maintain myoblasts in an undifferentiated/immature stage. To determine the relevance of these observations, we characterised the retinoic-acid-signalling pathways in freshly isolated satellite cells in mice and in siMYOD immature human myoblasts. Our analysis reveals that the immature state of muscle progenitors is correlated with high expression of several genes of the retinoic-acid-signalling pathway both in mice and in human. Taken together, our data provide evidences for an important role of the retinoic-acid-signalling pathway in the regulation of the immature state of muscle progenitors.

Muscle weakness is associated with increased mortality risk in chronic haemodialysis (CHD) patients. Protein energy wasting (PEW) and low physical activity could impair muscle quality and contribute to muscle weakness beyond muscle wasting in these patients. Aim of this study was to assess clinical and biological parameters involved in the reduction of muscle strength of CHD patients. One hundred and twenty-three CHD patients (80 males, 43 females; 68,8 [57.9-78.8] y.o.) were included in this study. Maximal voluntary force (MVF) of quadriceps was assessed using a belt-stabilized hand-held dynamometer. Muscle quality was evaluated by muscle specific torque, defined as the strength per unit of muscle mass. Muscle mass was estimated using lean tissue index (LTI), skeletal muscle mass (SMM) assessed by bioelectrical impedance analysis and creatinine index (CI). Voorrips questionnaire was used to estimate physical activity. Criteria for the diagnosis of PEW were serum albumin, body mass index < 23 kg/m2, creatinine index < 18.82 mg/kg/d and low dietary protein intake estimated by nPCR < 0.80g/kg/d. MVF was 76.1 [58.2-111.7] N.m. and was associated with CI (β = 5.3 [2.2-8.4], p = 0.001), LTI (β = 2.8 [0.6-5.1], p = 0.013), Voorrips score (β = 17.4 [2.9-31.9], p = 0.02) and serum albumin (β = 1.9 [0.5-3.2], p = 0.006). Only serum albumin (β = 0.09 [0.03-0.15], p = 0.003), Voorrips score (β = 0.8 [0.2-1.5], p = 0.005) and CI (β = 0.2 [0.1-0.3], p<0.001) remained associated with muscle specific torque. Thirty patients have dynapenia defined as impaired MVF with maintained SMM and were younger with high hs-CRP (p = 0.001), PEW criteria (p<0.001) and low Voorrips score (p = 0.001), and reduced dialysis vintage (p<0.046). Beyond atrophy, physical inactivity and PEW conspire to impair muscle strength and specific torque in CHD patients and could be related to muscle quality. ClinicalTrials.gov NCT02806089.

Facioscapulohumeral dystrophy (FSHD) is a muscular hereditary disease with a prevalence of 1 in 20,000 caused by a partial deletion of a subtelomeric repeat array on chromosome 4q. However, very little is known about the pathogenesis as well as the molecular and biochemical changes linked to the progressive muscle degeneration observed in these patients. Several studies have investigated possible pathophysiological pathways in FSHD myoblasts and mature muscle cells but some of these reports were apparently in contradiction. The discrepancy between these studies may be explained by differences between the sources of myoblasts. Therefore, we decided to thoroughly analyze affected and unaffected muscles from patients with FSHD in terms of vulnerability to oxidative stress, differentiation capacity and morphological abnormalities. We have established a panel of primary myoblast cell cultures from patients affected with FSHD and matched healthy individuals. Our results show that primary myoblasts are more susceptible to an induced oxidative stress than control myoblasts. Moreover, we demonstrate that both types of FSHD primary myoblasts differentiate into multi‐nucleated myotubes, which present morphological abnormalities. Whereas control myoblasts fuse to form branched myotubes with aligned nuclei, FSHD myoblasts fuse to form either thin and branched myotubes with aligned nuclei or large myotubes with random nuclei distribution. In conclusion, we postulate that these abnormalities could be responsible for muscle weakness in patients with FSHD and provide an important marker for FSHD myoblasts.

Polyphenols (PP) have demonstrated beneficial effects on low-grade inflammation and oxidative stress; however, little is known about their effect on highly inflamed muscle. The purposes of this study were (i) to evaluate muscle alteration induced by high-grade inflammation, and (ii) to test the effects of red grape PP supplementation on these alterations. We used a transgenic mice model (transforming growth factor [TGF] mice) to develop a high T cell–dependent inflammation and C57 BL/6 control (CTL) mice model. Skeletal muscles of TGF and CTL mice were investigated for inflammation, atrophy and oxidative stress markers. Isolated mitochondria from hindlimb muscles were used for respiration with pyruvate as substrate and oxidative damages were measured by Western blot. TGF mice were supplemented with a mixture of red grape polyphenols (50 mg/kg/d) for 4 wk. Data were analyzed by one-way analysis of variance (ANOVA) and post hoc Bonferroni's multiple comparison tests. TGF mice presented skeletal muscle inflammation, oxidative stress, mitochondrial alteration and muscle atrophy. Atrophy was associated with two distinct pathways: (i) one linked to inflammation, NF-κB activation and increased ubiquitin ligase expression, and (ii) one dependent on reactive oxygen species (ROS) production leading to damaged mitochondria accumulation and activation of caspase-9 and 3. Supplementation of TGF mice with a mixture of red grape polyphenols (50 mg/kg/d) for 4 wk improved mitochondrial function and highly decreased caspases activation, which allowed muscle atrophy mitigation. These observations suggest that nutritional dosages of red grape polyphenols might be beneficial for reducing skeletal muscle atrophy, even in a high-grade inflammation environment. •Highly inflamed transgenic mice presented skeletal muscle atrophy and mitochondrial dysfunction.•Polyphenols improved mitochondrial function and decreased caspases-9 and 3 activation.•The results of this study demonstrate that nutritional doses of red grape polyphenols mitigate atrophy.