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Background Undiagnosed atrial fibrillation (AF) exposes unsuspecting patients to elevated stroke risks. The optimal algorithm for identifying patients who should be screened for AF remains undetermined. The objective of this study is to determine the AF burden in an asymptomatic, at-risk population. We also sought to investigate potential predictors of undiagnosed AF. Methods This registry is a prospective observational study assessing continuous ECG monitoring in screening for AF using a wearable single lead 7-day continuous monitoring device. Patients included were asymptomatic individuals, at risk for AF as determined by either 1) ≥65 years of age with ≥1 high risk factor or; 2) ≥75 years of age and ≥2 moderate risk factors. A multivariable logistic regression was used to explore the predictive value of certain patient characteristics in identifying patients susceptible to have undiagnosed AF. Results Among the 942 patients included, 25 patients (2.7%) had evidence of AF detected. Only 8 patients had AF duration ≥24 h. History of perioperative AF (OR: 3.25, 95%CI: 1.08–9.79, p = 0.036), age over 85 (OR: 4.71, 95%CI: 1.31–16.92, p = 0.017) and absence of cardiovascular disease (CVD) (OR: 0.27, 95%CI: 0.10–0.76, p = 0.013) were found to be predictive of undiagnosed AF. Conclusion This study demonstrates the feasibility of office-based AF screening in at-risk population. The low rate of AF detection suggests that the optimal algorithm for identifying asymptomatic patients who would benefit from continuous screening remains unclear. Advanced age, history of perioperative AF and absence of CVD are variables that could be explored further.

Background Direct oral anticoagulants (DOACs) have been proven to be effective and safe for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). However, suboptimal adherence, variable dosing and use in patient populations that otherwise would have been excluded from clinical trials may impact the efficacy and safety profile of DOACs in a routine care setting. We compared stroke, bleeding, and mortality rates on and off therapy for standard and low-dose DOACs (apixaban, rivaroxaban, dabigatran) versus warfarin in a Canadian cohort. We also assessed persistence of DOACs compared to warfarin. Methods We conducted six 1-1 propensity-score matched retrospective cohort analyses using Quebec health administrative databases (2011–2017). NVAF patients (≥18 years) covered by the public medication insurance plan entered the cohort on the first OAC dispensation date. We excluded those with OAC use in the previous year or stroke or bleeding diagnoses in the previous two years. Follow-up ended at death, March 2017 or end of medication coverage by the public plan. Time-dependent Cox regression was applied. Results We evaluated 10,893 patients initiated on apixaban (7206 standard, 3687 low-dose), 10,190 on rivaroxaban (7396 standard, 2794 low-dose), 5884 on dabigatran (2756 standard, 3128 low-dose), and propensity score-matched warfarin users. Across standard-dose DOACs, compared to warfarin, stroke risks were similar; bleeding risks were lower with apixaban (hazard ratio 0.63; 95% confidence interval 0.52–0.77) and dabigatran (0.47; 0.35–0.64) but not rivaroxaban (0.93; 0.79–1.10); death risks were lower with all DOACs. For low-dose DOACs, rivaroxaban demonstrated higher stroke (1.79; 1.21–2.64) and bleeding risks (1.37; 1.09–1.73); other agents had stroke risks similar to warfarin and bleeding risks lower than warfarin; only low-dose dabigatran had lower death risk (0.59; 0.52–0.68). Treatment discontinuation was lower with DOACs versus warfarin with the exception of low-dose rivaroxaban. The risks of stroke were 2–4 folds higher during time off any OAC versus time on warfarin. The risks of death were higher, while the risks of bleeding were generally lower during times off any OAC. Conclusions Standard-dose DOACs had similar stroke, better persistence and mortality profiles than warfarin. Only standard dose apixaban and dabigatran had better bleeding profiles than warfarin. Low-dose rivaroxaban had worse persistence, stroke and bleeding profiles than warfarin, while low-dose apixaban and dabigatran had similar stroke and better bleeding profiles. Real-world use of DOACs may explain some of the differences observed in Canadian routine care versus the phase III clinical trials.

Background Atrial fibrillation is the most common arrhythmia seen in clinical practice, and is an important cause of stroke. In up to 10% of patients, stroke is the first clinical manifestation of undiagnosed atrial fibrillation (AF). Early detection of AF is therefore desirable, as it would provide an opportunity to initiate appropriate stroke prevention with anticoagulation. While European guidelines recommend screening for AF as part of routine care in patients with risk factors, the optimal modality has not yet been determined. Smartphone enabled single lead ECG devices have been shown to be highly accurate and could prove to be an effective point of care tool for uncovering AF in the community and may facilitate implementation of screening recommendations. Purpose We sought to describe the integration of a smartphone enabled single lead ECG device into the practice of selected Canadian community-based physicians and its impact on patient care. Methods Canadian community-based physicians were provided with a smartphone enabled single lead ECG device for a period of six months. Physicians were instructed to perform a single 30 second ECG recording in patients over the age of 65 who present for a regular follow-up visit. Patients with previous AF diagnosis were excluded. Outcomes related to screening, and stroke prevention-treatment initiation were prospectively ascertained and documented using a patient flow tracker. Results Among 612 physicians who were invited to participate in the program, 315 (51%) agreed to track and report the use of the device that was provided to them. During this program, 315 physicians screened a total of 15,538 patients. AF was detected 1103 patients (7.1%). The majority of patients with a positive screen underwent a subsequent 12-lead ECG confirmatory exam (79%). AF could not be confirmed in 277 patients (31.7% of patients undergoing 12-lead ECG). A total of 677 patients were initiated on oral anticoagulation (OAC), with 262 patients (24%) being initiated on OAC prior to ECG confirmation. Conclusion Undiagnosed AF is common in patients >65 years of age in community practice. The results of this program indicate that single lead mobile ECG devices can be integrated into routine point of care use for Canadian physicians and, can be a valuable tool to detect previously undiagnosed AF. While this approach identified a large number of undiagnosed AF patients eligible for OAC therapy, undertreatment with OAC remains a concern. Acknowledgement/Funding Bristol-Myers Squibb/Pfizer Alliance

Key points Parkin, an E3 ubiquitin ligase encoded by the Park2 gene, has been implicated in the regulation of mitophagy, a quality control process in which defective mitochondria are degraded. The exact physiological significance of Parkin in regulating mitochondrial function and contractility in skeletal muscle remains largely unexplored. Using Park2-/- mice, we show that Parkin ablation causes a decrease in muscle specific force, a severe decrease in mitochondrial respiration, mitochondrial uncoupling and an increased susceptibility to opening of the permeability transition pore. These results demonstrate that Parkin plays a protective role in the maintenance of normal mitochondrial and contractile functions in skeletal muscles. Abstract Parkin is an E3 ubiquitin ligase encoded by the Park2 gene. Parkin has been implicated in the regulation of mitophagy, a quality control process in which defective mitochondria are sequestered in autophagosomes and delivered to lysosomes for degradation. Although Parkin has been mainly studied for its implication in neuronal degeneration in Parkinson disease, its role in other tissues remains largely unknown. In the present study, we investigated the skeletal muscles of Park2 knockout (Park2-/- ) mice to test the hypothesis that Parkin plays a physiological role in mitochondrial quality control in normal skeletal muscle, a tissue highly reliant on mitochondrial content and function. We first show that the tibialis anterior (TA) of Park2-/- mice display a slight but significant decrease in its specific force. Park2-/- muscles also show a trend for type IIB fibre hypertrophy without alteration in muscle fibre type proportion. Compared to Park2+/+ muscles, the mitochondrial function of Park2-/- skeletal muscles was significantly impaired, as indicated by the significant decrease in ADP-stimulated mitochondrial respiratory rates, uncoupling, reduced activities of respiratory chain complexes containing mitochondrial DNA (mtDNA)-encoded subunits and increased susceptibility to opening of the permeability transition pore. Muscles of Park2-/- mice also displayed a decrease in the content of the mitochondrial pro-fusion protein Mfn2 and an increase in the pro-fission protein Drp1 suggesting an increase in mitochondrial fragmentation. Finally, Park2 ablation resulted in an increase in basal autophagic flux in skeletal muscles. Overall, the results of the present study demonstrate that Parkin plays a protective role in the maintenance of normal mitochondrial and contractile functions in normal skeletal muscles.

Background Atrial fibrillation (AF), which affects 1% to 4% of the general population, is an important risk factor for stroke. New technologies for AF screening are now available, but their real-world application in clinical settings has not yet been thoroughly investigated. The aim of this project was to describe the introduction and feasibility of a mobile electrocardiogram (ECG) device for AF screening in a large-scale, undifferentiated population. Methods A total of 184 Canadian primary care physicians were provided with a KardiaMobile ECG device (AliveCor) for 3 months. Physicians were asked to obtain a single 30-second ECG recording of all patients seen in their daily practice who were ≥65 years old and not previously diagnosed with AF. Evaluation of the Kardia device by physicians was measured using a Likert scale–based questionnaire. Results One hundred thirty-three physicians (72%) reported their findings and completed the survey. A total of 7585 patients were screened (42% of eligible patients). AF was detected in 471 patients (6.2%). Anticoagulation therapy was initiated in 270 patients (57%). Physicians generally reported a high perceived clinical value (94%) and ease of integration (89%) of the device. Conclusions Previously undiagnosed AF is common in older individuals attending primary care clinics. The KardiaMobile ECG device appears to be an effective screening tool for AF with high physician acceptability. More research on the feasibility of such novel technologies is warranted for future consideration of integration in population-based screening programs.

Danazol has been used in the treatment of endometriosis and heavy menstrual bleeding for more than 40 years. This medication has both central antigonadotropic actions and direct atrophic effects on endometriotic tissue. Although it demonstrates a high-efficacy profile, the associated side effects have resulted in limited usage. Vaginal administration of the drug may prove favourable specifically in rectovaginal endometriosis. This targeted mode of delivery is associated with a significant reduction in both pain symptoms and nodule size. The relative persistence of these therapeutic benefits is likely related to the direct tissue effects after absorption through the vaginal mucosa. Vaginal administration would also limit systemic propagation of danazol and thus should minimize androgenic side effects. Use of vaginal danazol also improves heavy menstrual bleeding and may even restore fertility in some patients. In this review we provide a critical analysis of the existing literature on the use of vaginal danazol.Le danazol est utilisé dans la prise en charge de l’endométriose et des saignements menstruels abondants depuis plus de 40 ans. Ce médicament exerce tant des effets antigonadotropes centraux que des effets atrophiques directs sur le tissu endométriotique. Bien qu’il présente un profil solide d’efficacité, les effets indésirables qui lui sont associés en ont limité l’utilisation. L’administration de ce médicament par voie vaginale pourrait s’avérer favorable, particulièrement dans les cas d’endométriose rectovaginale. Ce mode d’administration ciblée est associé à une atténuation significative des symptômes de douleur et de la taille des nodules. La persistance relative de ces avantages thérapeutiques est probablement associée aux effets tissulaires directs qui sont constatés à la suite de l’absorption au travers de la muqueuse vaginale. L’administration par voie vaginale permettrait également de limiter la propagation générale du danazol, ce qui devrait en minimiser les effets indésirables androgéniques. L’utilisation de danazol par voie vaginale entraîne également une atténuation des saignements menstruels abondants et pourrait même restaurer la fertilité chez certaines patientes. Dans le cadre de cet article, nous offrons une analyse critique de la littérature existante sur l’utilisation du danazol par voie vaginale.

Women who are receiving an oral anticoagulant appear to be at higher risk of developing bleeding-related adverse events than men. Physiological bleeding related to the ovulatory cycle poses an ongoing risk for bleeding complications during anticoagulant therapy. Abnormal uterine bleeding and hemorrhagic ovarian cysts are risks specific to women of reproductive age who are treated with anticoagulants. The use of combined oral contraceptives can help minimize such adverse events and would also mitigate the risks of obstetrical complications related to thrombosis and anticoagulation, in addition to avoiding fetal exposure to potentially teratogenic anticoagulants. Clinicians tend to interrupt oral contraceptives in women who are receiving oral anticoagulants despite the absence of evidence that they increase thrombotic risks when taken concurrently. This letter of opinion aims to support the use of oral contraceptives, when clinically indicated, in women of reproductive age who also are receiving an oral anticoagulant.

Parkin, an E3 ubiquitin ligase encoded by the Park2 gene, has been implicated in the regulation of mitophagy, a quality control process in which defective mitochondria are degraded. The exact physiological significance of Parkin in regulating mitochondrial function and contractility in skeletal muscle remains largely unexplored. Using Park2Parkin is an E3 ubiquitin ligase encoded by the Park2 gene. Parkin has been implicated in the regulation of mitophagy, a quality control process in which defective mitochondria are sequestered in autophagosomes and delivered to lysosomes for degradation. Although Parkin has been mainly studied for its implication in neuronal degeneration in Parkinson disease, its role in other tissues remains largely unknown. In the present study, we investigated the skeletal muscles of Park2 knockout (Park2

Partant d’evenements distincts dans le temps et l’espace, mais lies par essence, la memoire historique se deploie, laissant apparaitre au present un passe aux contours incertains. A deux reprises, en 1982 et en 1985, l’ambassade de Turquie au Canada est le theâtre d’attentats : des « terroristes d’origine armenienne » signent des actes violents causant mort d’hommes, afin que la Turquie reconnaisse sa responsabilite dans le genocide des Armeniens en 19151. Ces evenements, qui relevent alors de l’actualite, reactivent la construction memorielle du genocide des Armeniens dans l’espace public. Les medias, la presse ecrite en l’occurrence, pris entre les evenements presents et passes, s’evertuent alors a faire etat du genocide, de ses faits, de son oubli, de son deni par les autorites turques et une partie de la communaute internationale. Des lors, la memoire mediatique joue de l’histoire, episodiquement, faisant passer de l’ombre a la lumiere des faits classes en attente d’un jugement, si bien qu’elle participe parfois de la guerre des memoires et des usages politiques du passe. Dans une perspective memorielle, il serait d’interet d’examiner le role tenu alors par les medias dans la relation des faits. A cet egard, l’epistemologie des sciences de l’information fixe des limites quant aux fonctions traditionnelles de la presse, lesquelles determineront toujours la maniere de relater les faits. D’ou la pertinence d’examiner, d’un point de vue anthropologique, l’hypothese voulant qu

Abnormal uterine bleeding (AUB) is a common complication of anticoagulant therapy in premenopausal women affected with acute venous thromboembolism. AUB impacts quality of life, and can lead to premature cessation of anticoagulation. There is increasing data to suggest that the direct oral anticoagulants when used for the treatment of venous thromboembolism differ in their menstrual bleeding profile. This article aims to review the existing literature regarding the association between AUB and the direct oral anticoagulants and make practical recommendations.

Autophagy is an important proteolytic pathway in skeletal muscles. The roles of muscle fiber type composition and oxidative capacity remain unknown in relation to autophagy. The diaphragm (DIA) is a fast-twitch muscle fiber with high oxidative capacity, the tibialis anterior (TA) muscle is a fast-twitch muscle fiber with low oxidative capacity, and the soleus muscle (SOL) is a slow-twitch muscle with high oxidative capacity. We hypothesized that oxidative capacity is a major determinant of autophagy in skeletal muscles. Following acute (24 h) starvation of adult C57/Bl6 mice, each muscle was assessed for autophagy and compared with controls. Autophagy was measured by monitoring autophagic flux following leupeptin (20 mg/kg) or colchicine (0.4 mg/kg/day) injection. Oxidative capacity was measured by monitoring citrate synthase activity. In control mice, autophagic flux values were significantly greater in the TA than in the DIA and SOL. In acutely starved mice, autophagic flux increased, most markedly in the TA, and several key autophagy-related genes were significantly induced. In both control and starved mice, there was a negative linear correlation of autophagic flux with citrate synthase activity. Starvation significantly induced AMPK phosphorylation and inhibited AKT and RPS6KB1 phosphorylation, again most markedly in the TA. Starvation induced Foxo1, Foxo3, and Foxo4 expression and attenuated the phosphorylation of their gene products. We conclude that both basal and starvation-induced autophagic flux are greater in skeletal muscles with low oxidative capacity as compared with those with high oxidative capacity and that this difference is mediated through selective activation of the AMPK pathway and inhibition of the AKT-MTOR pathways.

After reading the elegant review by Steinberg et al. [(1)][1] on maternal and fetal outcomes of anticoagulation in pregnant women with mechanical heart valves (MHVs), we remain undecided on the best anticoagulation regimen for these patients. We would like to offer in response to this review a

Key points • Mitochondria are increasingly implicated in the pathogenesis of Duchenne muscular dystrophy (DMD). However, the extent to which the multiple facets of mitochondrial function are altered remains uncertain due to the lack of detailed assessment. • Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) was recently shown to improve muscle pathology in dystrophic muscle. However, the mechanisms are not fully elucidated. • This study provides novel information on mitochondrial dysfunction in DMD namely that (i) loss of mitochondrial biomass precedes overt respiratory abnormalities, (ii) mitochondrial H2O2 metabolism is improved at a time when no oxidative damage is detectable in the muscle, and (iii) susceptibility to permeability transition pore (PTP) opening is increased, which has only been inferred in the past, but never actually measured. • This study also provides new mechanistic information regarding the beneficial effects of PGC1α overexpression upon dystrophic muscles, namely that PGC1α not only increases mitochondrial biomass but also reduces PTP opening, improves mitochondrial Ca2+ handling and reduces the activation of Ca2+ and mitochondria-dependent proteases in muscles of mdx mice. These mechanisms were not examined in previous investigations, which had largely attributed the improved histopathology after PGC1α therapy to utrophin upregulation. Abstract Alterations of mitochondrial function have been implicated in the pathogenesis of Duchenne muscular dystrophy. In the present study, mitochondrial respiratory function, reactive oxygen species (ROS) dynamics and susceptibility to Ca2+-induced permeability transition pore (PTP) opening were investigated in permeabilized skeletal muscle fibres of 6-week-old mdx mice, in order to characterize the magnitude and nature of mitochondrial dysfunction at an early post-necrotic stage of the disease. Short-term overexpression of the transcriptional co-activator PGC1α, achieved by in vivo plasmid transfection, was then performed to determine whether this intervention could prevent mitochondrial impairment and mitigate associated biochemical abnormalities. Compared with normal mice, mdx mice exhibited a lower mitochondrial biomass and oxidative capacity, greater ROS buffering capabilities, and an increased vulnerability to Ca2+-induced opening of the mitochondrial permeability transition pore complex. PGC1α gene transfer restored mitochondrial biomass, normalized the susceptibility to PTP opening and increased the capacity of mitochondria to buffer Ca2+. This was associated with reductions in the activity levels of the Ca2+-dependent protease calpain as well as caspases 3 and 9. Overall, these results suggest that overexpression of PGC1α in dystrophin-deficient muscles, after the onset of necrosis, has direct beneficial effects upon multiple aspects of mitochondrial function, which may in turn mitigate the activation of proteolytic and apoptotic signalling pathways associated with disease progression.

The First World War brought extreme violence to the battlefields of Europe and to its civilian population. Following the invasion of Belgium and northern France, during the summer and fall of 1914, German troops resorted to abuses and slaughter against Belgian and French civilians (Horne & Kramer, 2001). French, Belgian and British authorities quickly set up inquiries, and they produced reports denouncing “German atrocities.” A few months later, in the spring of 1915, news from the Ottoman Empire described systematic massacres, wide-scale deportations and the slaughtering of the Armenian civil population (Kevorkian, 2011). In May 1915, in a joint statement, the Triple Entente — France, Great Britain and Russia — accused the Turkish government of “crimes against humanity and civilization” (Racine, 2006: 3–8).

In 1915, one of the first genocides in contemporary history was witnessed by representatives of powerful countries such as the United States of America, Italy, Germany, and Russia. Between April 15, 1915 and November 1916, at least 1.5 million Armenians were massacred on Turkish territory, as ordered by the government. When this news was made public in international newspapers, it was already too late to intervene. The Armenian population of Turkey was in the process of being exterminated. The process was put in place in March 1915 by order of the Turkish government itself, headed by the Young Turk Revolution Party and its main leaders Ismail Enver Pasha and Mehmed Talaat Pasha.

In the present study, we specifically determined whether the regulatory protein cyclophilin-D (CypD), and by extension opening of the permeability transition pore (PTP), is involved in the activation of mitochondria-derived apoptotic signalling previously described in skeletal muscle following loss of innervation. For this purpose, CypD-defficient (CypD-KO) mice and their littermate controls were submitted to unilateral sciatic nerve transection, and mitochondrial resistance to Ca2+-induced opening of the PTP, and muscle apoptotic signalling were investigated 14 days post-surgery. Denervation caused atrophy, facilitated Ca2+-induced opening of the PTP in vitro in permeabilized muscle fibres, and activation of the apoptotic proteolytic cascade in the whole muscle of both mouse strains. In CypD-KO mice, mitochondrial resistance to Ca2+-induced PTP opening was greater than in WT mice, in both the normal and the denervated state, indicating that lack of CypD desensitized to PTP opening. However, denervation in CypD-KO mice still resulted in a facilitation of PTP opening compared to normally innervated contralateral muscle, indicating that in vitro additional factors could poise mitochondria from denervated muscle toward PTP opening. At the whole muscle level, lack of CypD, despite conferring greater resistance to PTP opening, did not protect against atrophy, release of mitochondrial pro-apoptotic factors and activation of caspases following denervation. Altogether, these results provide direct evidence that CypD-dependent PTP opening is dispensable for atrophy and apoptotic signalling in skeletal muscle following denervation.

This study determined whether susceptibility to opening of the permeability transition pore (PTP) varies according to muscle phenotype represented by the slow oxidative soleus (Sol) and superficial white gastrocnemius (WG). Threshold for Ca2+-induced mitochondrial Ca2+ release following PTP opening was determined with a novel approach using permeabilized ghost myofibers. Threshold values for PTP opening were approximately threefold higher in fibers from WG compared with those from Sol (124 ± 47 vs. 30.4 ± 6.8 pmol Ca2+/mU citrate synthase). A similar phenomenon was also observed in isolated mitochondria (threshold: 121 ± 60 vs. 40 ± 10 nmol Ca2+/mg protein in WG and Sol), indicating that this was linked to differences in mitochondrial factors between the two muscles. The resistance of WG fibers to PTP opening was not related to the expression of putative protein modulators (cyclophilin D, adenylate nucleotide translocator-1, and voltage-dependent anion channels) or to difference in respiratory properties and occurred despite the fact that production of reactive oxygen species, which promote pore opening, was higher than in the Sol. However, endogenous matrix Ca2+ measured in mitochondria isolated under resting baseline conditions was approximately twofold lower in the WG than in the Sol (56 ± 4 vs. 111 ± 11 nmol/mg protein), which significantly accounted for the resistance of WG. Together, these results reveal fiber type differences in the sensitivity to Ca2+-induced PTP opening, which may constitute a physiological mechanism to adapt mitochondria to the differences in Ca2+ dynamics between fiber types.

Mitochondrial quality control plays a vital role in the maintenance of optimal mitochondrial function. However, its roles and regulation remain ill-defined in cardiac pathophysiology. Here, we tested the hypothesis that PARK2/Parkin, an E3-ligase recently described as being involved in the regulation of cardiac mitophagy, is important for (1) the maintenance of normal cardiac mitochondrial function; and (2) adequate recovery from sepsis, a condition known to induce reversible mitochondrial injury through poorly understood mechanisms. Investigations of mitochondrial and cardiac function were thus performed in wild-type and Park2-deficient mice at baseline and at 2 different times following administration of a sublethal dose of E. coli lipopolysaccharide (LPS). LPS injection induced cardiac and mitochondrial dysfunctions that were followed by complete recovery in wild-type mice. Recovery was associated with morphological and biochemical evidence of mitophagy, suggesting that this process is implicated in cardiac recovery from sepsis. Under baseline conditions, multiple cardiac mitochondrial dysfunctions were observed in Park2-deficient mice. These mild dysfunctions did not result in a visibly distinct cardiac phenotype. Importantly, Park2-deficient mice exhibited impaired recovery of cardiac contractility and constant degradation of mitochondrial metabolic functions. Interestingly, autophagic clearance of damaged mitochondria was still possible in the absence of PARK2 likely through compensatory mechanisms implicating PARK2-independent mitophagy and upregulation of macroautophagy. Together, these results thus provide evidence that in vivo, mitochondrial autophagy is activated during sepsis, and that compensation for a lack of PARK2 is only partial and/or that PARK2 exerts additional protective roles in mitochondria.

Rationale Mechanical ventilation (MV) is associated with adverse effects on the diaphragm, but the cellular basis for this phenomenon, referred to as ventilator-induced diaphragmatic dysfunction (VIDD), is poorly understood. Objectives To determine whether mitochondrial function and cellular energy status are disrupted in human diaphragms after MV, and the role of mitochondria-derived oxidative stress in the development of VIDD. Methods Diaphragm and biceps specimens obtained from brain-dead organ donors who underwent MV (15-176 h) and age-matched control subjects were compared regarding mitochondrial enzymatic function, mitochondrial DNA integrity, lipid content, and metabolic gene and protein expression. In addition, diaphragmatic force and oxidative stress after exposure to MV for 6 hours were evaluated in mice under different conditions. Measurements and main results In human MV diaphragms, mitochondrial biogenesis and content were down-regulated, with a more specific defect of respiratory chain cytochrome-c oxidase. Laser capture microdissection of cytochrome-c oxidase-deficient fibers revealed mitochondrial DNA deletions, consistent with damage from oxidative stress. Diaphragmatic lipid accumulation and responses of master cellular metabolic sensors (AMP-activated protein kinase and sirtuins) were consistent with energy substrate excess as a possible stimulus for these changes. In mice, induction of hyperlipidemia worsened diaphragmatic oxidative stress during MV, whereas transgenic overexpression of a mitochondria-localized antioxidant (peroxiredoxin-3) was protective against VIDD. Conclusions Our data suggest that mitochondrial dysfunction lies at the nexus between oxidative stress and the impaired diaphragmatic contractility that develops during MV. Energy substrate oversupply relative to demand, resulting from diaphragmatic inactivity during MV, could play an important role in this process.

Background Mitochondrial injury develops in skeletal muscles during the course of severe sepsis. Autophagy is a protein and organelle recycling pathway which functions to degrade or recycle unnecessary, redundant, or inefficient cellular components. No information is available regarding the degree of sepsis-induced mitochondrial injury and autophagy in the ventilatory and locomotor muscles. This study tests the hypotheses that the locomotor muscles are more prone to sepsis-induced mitochondrial injury, depressed biogenesis and autophagy induction compared with the ventilatory muscles. Methodology/Principal Findings Adult male C57/Bl6 mice were injected with i.p. phosphate buffered saline (PBS) or E. coli lipopolysaccharide (LPS, 20 mg/kg) and sacrificed 24 h later. The tibialis anterior (TA), soleus (SOLD) and diaphragm (DIA) muscles were quickly excised and examined for mitochondrial morphological injury, Ca++ retention capacity and biogenesis. Autophagy was detected with electron microscopy, lipidation of Lc3b proteins and by measuring gene expression of several autophagy-related genes. Electron microscopy revealed ultrastructural injuries in the mitochondria of each muscle, however, injuries were more severe in the TA and SOL muscles than they were in the DIA. Gene expressions of nuclear and mitochondrial DNA transcription factors and co-activators (indicators of biogenesis) were significantly depressed in all treated muscles, although to a greater extent in the TA and SOL muscles. Significant autophagosome formation, Lc3b protein lipidation and upregulation of autophagy-related proteins were detected to a greater extent in the TA and SOL muscles and less so in the DIA. Lipidation of Lc3b and the degree of induction of autophagy-related proteins were significantly blunted in mice expressing a muscle-specific IκBα superrepresor. Conclusion/Significance We conclude that locomotor muscles are more prone to sepsis-induced mitochondrial injury, decreased biogenesis and increased autophagy compared with the ventilatory muscles and that autophagy in skeletal muscles during sepsis is regulated in part through the NFκB transcription factor.

International audience; Duchenne muscular dystrophy (DMD) is characterized by myofiber death from apoptosis or necrosis, leading in many patients to fatal respiratory muscle weakness. Among other pathological features, DMD muscles show severely deranged metabolic gene regulation and mitochondrial dysfunction. Defective mitochondria not only cause energetic deficiency, but also play roles in promoting myofiber atrophy and injury via opening of the mitochondrial permeability transition pore. Autophagy is a bulk degradative mechanism that serves to augment energy production and eliminate defective mitochondria (mitophagy). We hypothesized that pharmacological activation of AMP-activated protein kinase (AMPK), a master metabolic sensor in cells and on-switch for the autophagy-mitophagy pathway, would be beneficial in the mdx mouse model of DMD. Treatment of mdx mice for 4 weeks with an established AMPK agonist, AICAR (5-aminoimidazole-4-caboxamide-1-beta-D-ribofuranoside), potently triggered autophagy in the mdx diaphragm without inducing muscle fiber atrophy. In AICAR-treated mdx mice, the exaggerated sensitivity of mdx diaphragm mitochondria to calcium-induced permeability transition pore opening was restored to normal levels. There were associated improvements in mdx diaphragm histopathology and in maximal force-generating capacity, which were not linked to increased mitochondrial biogenesis or up-regulated utrophin expression. These findings suggest that agonists of AMPK and other inducers of the autophagy-mitophagy pathway can help to promote the elimination of defective mitochondria and may thus serve as useful therapeutic agents in DMD. (Am J Path, 2012, 181:583-592; http://dx.doi.org/10.1016/j.ajpath.2012.04.004)

Susceptibility of cardiomyocytes to stress-induced damage has been implicated in the development of cardiomyopathy in Duchenne muscular dystrophy, a disease caused by the lack of the cytoskeletal protein dystrophin in which heart failure is frequent. However, the factors underlying the disease progression are unclear and treatments are limited. Here, we tested the hypothesis of a greater susceptibility to the opening of the mitochondrial permeability transition pore (PTP) in hearts from young dystrophic ( mdx) mice (before the development of overt cardiomyopathy) when subjected to a stress protocol and determined whether the prevention of a PTP opening is involved in the cardioprotective effect of sildenafil, which we have previously reported in mdx mice. Using the 2-deoxy-[3H]glucose method to quantify the PTP opening in ex vivo perfused hearts, we demonstrate that when compared with those of controls, the hearts from young mdx mice subjected to ischemia-reperfusion (I/R) display an excessive PTP opening as well as enhanced activation of cell death signaling, mitochondrial oxidative stress, cardiomyocyte damage, and poorer recovery of contractile function. Functional analyses in permeabilized cardiac fibers from nonischemic hearts revealed that in vitro mitochondria from mdx hearts display normal respiratory function and reactive oxygen species handling, but enhanced Ca2+ uptake velocity and premature opening of the PTP, which may predispose to I/R-induced injury. The administration of a single dose of sildenafil to mdx mice before I/R prevented excessive PTP opening and its downstream consequences and reduced tissue Ca2+ levels. Furthermore, mitochondrial Ca2+ uptake velocity was reduced following sildenafil treatment. In conclusion, beyond our documentation that an increased susceptibility to the opening of the mitochondrial PTP in the mdx heart occurs well before clinical signs of overt cardiomyopathy, our results demonstrate that sildenafil, which is already administered in other pediatric populations and is reported safe and well tolerated, provides efficient protection against this deleterious event, likely by reducing cellular Ca2+ loading and mitochondrial Ca2+ uptake.

Physical activity elicits physiological responses in skeletal muscle that result in a number of health benefits, in particular in diseases associated with peripheral metabolic dysfunction such as diabetes, heart failure or chronic obstructive pulmonary disease. These diseases have been associated with altered skeletal muscle metabolism and, in some cases, diminished ATP production, decreased mitochondrial content, and a higher proportion of type II fast glycolytic fibre. Exercise training is one intervention that can increase the percentage of oxidative fibres (type I, slow) and have a beneficial impact on these disease states. Several studies have compared the effects of continuous vs. interval training, and have determined that interval training may be the most effective exercise strategy to promote mitochondrial biogenesis and enhance muscle oxidative capacity. The importance of exercise in regulating skeletal muscle metabolism is well appreciated; however, the molecular mechanisms that underlie the beneficial adaptations to exercise remain to be fully understood. Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is a key factor involved in the regulation of multiple myocellular signalling pathways such as those implicated in mitochondrial biogenesis and fibre type expression (Russell et al. 2003). Although muscle contraction is known to strongly modulate PGC-1α expression in human skeletal muscle, little is known about the underlying intracellular mechanisms involved. The differential activation across varying training protocols may shed light onto the regulation of signalling pathways upstream of PGC-1α. This Journal Club article discusses the paper of Egan et al. (2010) published recently in The Journal of Physiology and suggests that differences in fibre type recruitment may explain some of the results. Egan et al. compared the effects two isocaloric bouts of exercise performed at either low or high intensity on skeletal muscle signalling. Eight sedentary males performed two trials on a stationary ergocycle: the low- and high-intensity exercise consisted of continuous cycling at 40% or 80% of peak oxygen consumption (), respectively, until the caloric expenditure reached 400 kcal (1674 kJ). Muscle biopsies from the vastus lateralis were taken at rest and at +0, +3 and +19 h after both exercise bouts. The dietary intake during each experimental trial was controlled. PGC-1α mRNA increased 3 h after both exercise bouts; they observed a 3.8-fold increase after low-intensity exercise whereas it increased 10.2-fold after high-intensity training, supporting an intensity-dependent regulation of PGC-1α expression. The authors also explored the signalling pathways upstream of PGC-1α. Protein quantification by immunoblotting revealed a differential activation of multiple signalling pathways involved directly and indirectly in the regulation of PGC-1α transcription. The higher PGC-1α mRNA abundance after high-intensity exercise also coincided with a greater phosphorylation of activating transcription factor-2 (ATF-2) and of class IIa histone deacetylase (HDAC) proteins also suggesting that ATF-2 and HDAC proteins were involved in an intensity-dependent manner. The authors concluded that the intensity during a single bout of exercise regulates PGC-1α mRNA abundance by activating selected upstream signalling pathways in human skeletal muscle with an intensity-dependent response.

Cet article s’interesse a la maniere avec laquelle les resultats aux referendums francais et neerlandais sur la Constitution europeenne sont interpretes dans la presse anglo-canadienne et franco-quebecoise a l’aune des recentes crises constitutionnelles. Les quotidiens ont ajuste leur « focale mediatique » en fonction de leur comprehension locale de l’evenement, de sa mise en marche, de son usage politique, voire de la constitution de communautes emotionnelles. Ainsi, les journaux anglo-canadiens cantonneraient l’evenement au temps tres court de l’actualite quotidienne, alors que les franco-quebecois privilegieraient une trame temporelle plus longue.

Aging-related loss of muscle mass, a biological process named sarcopenia, contributes to mobility impairment, falls, and physical frailty, resulting in an impaired quality of life in older people. In view of the aging of our society, understanding the underlying mechanisms of sarcopenia is a major health-care imperative. Evidence obtained from human and rodent studies demonstrates that skeletal muscle denervation/reinnervation cycles occur with aging, and that progressive failure of myofiber reinnervation is a major cause of the accelerating phase of sarcopenia in advanced age. However, the mechanisms responsible for the loss of myofiber innervation with aging remain unknown. The two major strategies that counteract sarcopenia, that is, caloric restriction and endurance training, are well known to protect neuromuscular junction (NMJ) integrity, albeit through undefined mechanisms. Interestingly, both of these interventions better preserve PGC-1α expression with aging, a transcriptional coactivator which has recently been shown to regulate key proteins involved in maintaining NMJ integrity. We therefore propose that the aging-related decline in PGC-1α may be a central mechanism promoting instability of the NMJ and consequently, aging-related alterations of myofiber innervation in sarcopenia. Similarly, the promotion of PGC-1α expression by both caloric restriction and exercise training may be fundamental to their protective benefits for aging muscle by better preserving NMJ integrity.