Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a ‘mitohormesis' mechanism involving reactive oxygen species and PGC-1

Aims Statins protect against cardiovascular-related mortality but induce skeletal muscle toxicity. To investigate mechanisms of statins, we tested the hypothesis that statins optimized cardiac mitochondrial function but impaired vulnerable skeletal muscle by inducing different level of reactive oxygen species (ROS). Methods and results In atrium of patients treated with statins, ROS production was decreased and oxidative capacities were enhanced together with an extensive augmentation of mRNAs expression of peroxisome proliferator-activated receptor gamma co-activator (PGC-1) family. However, in deltoid biopsies from patients with statin-induced muscular myopathy, oxidative capacities were decreased together with ROS increase and a collapse of PGC-1 mRNA expression. Several animal and cell culture experiments were conducted and showed by using ROS scavengers that ROS production was the triggering factor responsible of atorvastatin-induced activation of mitochondrial biogenesis pathway and improvement of antioxidant capacities in heart. Conversely, in skeletal muscle, the large augmentation of ROS production following treatment induced mitochondrial impairments, and reduced mitochondrial biogenesis mechanisms. Quercetin, an antioxidant molecule, was able to counteract skeletal muscle deleterious effects of atorvastatin in rat. Conclusion Our findings identify statins as a new activating factor of cardiac mitochondrial biogenesis and antioxidant capacities, and suggest the importance of ROS/PGC-1 signalling pathway as a key element in regulation of mitochondrial function in cardiac as well as skeletal muscle

Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a 'mitohormesis' mechanism involving reactive oxygen species and PGC-1

Aims Statins protect against cardiovascular-related mortality but induce skeletal muscle toxicity. To investigate mechanisms of statins, we tested the hypothesis that statins optimized cardiac mitochondrial function but impaired vulnerable skeletal muscle by inducing different level of reactive oxygen species (ROS). Methods and results In atrium of patients treated with statins, ROS production was decreased and oxidative capacities were enhanced together with an extensive augmentation of mRNAs expression of peroxisome proliferator-activated receptor gamma co-activator (PGC-1) family. However, in deltoid biopsies from patients with statin-induced muscular myopathy, oxidative capacities were decreased together with ROS increase and a collapse of PGC-1 mRNA expression. Several animal and cell culture experiments were conducted and showed by using ROS scavengers that ROS production was the triggering factor responsible of atorvastatin-induced activation of mitochondrial biogenesis pathway and improvement of antioxidant capacities in heart. Conversely, in skeletal muscle, the large augmentation of ROS production following treatment induced mitochondrial impairments, and reduced mitochondrial biogenesis mechanisms. Quercetin, an antioxidant molecule, was able to counteract skeletal muscle deleterious effects of atorvastatin in rat. Conclusion Our findings identify statins as a new activating factor of cardiac mitochondrial biogenesis and antioxidant capacities, and suggest the importance of ROS/PGC-1 signalling pathway as a key element in regulation of mitochondrial function in cardiac as well as skeletal muscles

Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) is mainly caused by homozygous SMN1 gene deletions on 5q13. Non-5q SMA patients' series are lacking, and the diagnostic yield of next-generation sequencing (NGS) is largely unknown. The aim of this study was to describe the clinical and genetic landscape of non-5q SMA and evaluate the performance of neuropathy gene panels in these disorders. METHODS: Description of patients with non-5q SMA followed in the different neuromuscular reference centers in France as well as in London, United Kingdom. Patients without a genetic diagnosis had undergone at least a neuropathy or large neuromuscular gene panel. RESULTS: Seventy-one patients from 65 different families were included, mostly sporadic cases (60.6%). At presentation, 21 patients (29.6%) showed exclusive proximal weakness (P-SMA), 35 (49.3%) showed associated distal weakness (PD-SMA), and 15 (21.1%) a scapuloperoneal phenotype (SP-SMA). Thirty-two patients (45.1%) had a genetic diagnosis: BICD2 (n = 9), DYNC1H1 (n = 7), TRPV4 (n = 4), VCP, HSBP1, AR (n = 2), VRK1, DNAJB2, MORC2, ASAH1, HEXB, and unexpectedly, COL6A3 (n = 1). The genetic diagnostic yield was lowest in P-SMA (6/21, 28.6%) compared with PD-SMA (16/35, 45.7%) and SP-SMA (10/15, 66.7%). An earlier disease onset and a family history of the disease or consanguinity were independent predictors of a positive genetic diagnosis. Neuropathy gene panels were performed in 59 patients with a 32.2% diagnostic yield (19/59). In 13 additional patients, a genetic diagnosis was achieved through individual gene sequencing or an alternative neuromuscular NGS. DISCUSSION: Non-5q SMA is genetically heterogeneous, and neuropathy gene panels achieve a molecular diagnosis in one-third of the patients. The diagnostic yield can be increased by sequencing of other neuromuscular and neurometabolic genes. Nevertheless, there is an unmet need to cluster these patients to aid in the identification of new genes

Guillain-Barre syndrome after SARS-CoV-2 infection in an international prospective cohort study

In the wake of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, an increasing number of patients with neurological disorders, including Guillain-Barre syndrome (GBS), have been reported following this infection. It remains unclear, however, if these cases are coincidental or not, as most publications were case reports or small regional retrospective cohort studies. The International GBS Outcome Study is an ongoing prospective observational cohort study enrolling patients with GBS within 2 weeks from onset of weakness. Data from patients included in this study, between 30 January 2020 and 30 May 2020, were used to investigate clinical and laboratory signs of a preceding or concurrent SARS-CoV-2 infection and to describe the associated clinical phenotype and disease course. Patients were classified according to the SARS-CoV-2 case definitions of the European Centre for Disease Prevention and Control and laboratory recommendations of the World Health Organization. Forty-nine patients with GBS were included, of whom eight (16%) had a confirmed and three (6%) a probable SARS-CoV-2 infection. Nine of these 11 patients had no serological evidence of other recent preceding infections associated with GBS, whereas two had serological evidence of a recent Campylobacter jejuni infection. Patients with a confirmed or probable SARS-CoV-2 infection frequently had a sensorimotor variant 8/11 (73%) and facial palsy 7/11 (64%). The eight patients who underwent electrophysiological examination all had a demyelinating subtype, which was more prevalent than the other patients included in the same time window [14/30 (47%), P = 0.012] as well as historical region and age-matched control subjects included in the International GBS Outcome Study before the pandemic [23/44 (52%), P = 0.016]. The median time from the onset of infection to neurological symptoms was 16 days (interquartile range 12-22). Patients with SARS-CoV-2 infection shared uniform neurological features, similar to those previously described in other post-viral GBS patients. The frequency (22%) of a preceding SARS-CoV-2 infection in our study population was higher than estimates of the contemporaneous background prevalence of SARS-CoV-2, which may be a result of recruitment bias during the pandemic, but could also indicate that GBS may rarely follow a recent SARS-CoV-2 infection. Consistent with previous studies, we found no increase in patient recruitment during the pandemic for our ongoing International GBS Outcome Study compared to previous years, making a strong relationship of GBS with SARS-CoV-2 unlikely. A case-control study is required to determine if there is a causative link or not

Study of mitochondrial function and Nogo gene expression in skeletal muscle in human sporadic amyotrophic lateral sclerosis

La sclérose latérale amyotrophique (SLA) est une affection mortelle caractérisée par une dégénérescence des motoneurones. Il s'agit habituellement une affection sporadique d'étiologie inconnue et pour laquelle il n'existe pas de marqueur diagnostique spécAmyotrophic lateral sclerosis (ALS) is a lethal disease characterized by degeneration of motoneurons. ALS is usually a sporadic condition of unknown origin. No specific diagnostic marker of ALS exists. It was recently proposed that mitochondrial abnormal

Study of mitochondrial function and Nogo gene expression in skeletal muscle in human sporadic amyotrophic lateral sclerosis

La sclérose latérale amyotrophique (SLA) est une affection mortelle caractérisée par une dégénérescence des motoneurones. Il s'agit habituellement une affection sporadique d'étiologie inconnue et pour laquelle il n'existe pas de marqueur diagnostique spécifique. Il a été récemment suggéré qu un dysfonctionnement mitochondrial pourrait être impliqué dans la physiopathologie de la SLA. Dans ce travail, nous avons réalisé une étude temporelle du fonctionnement mitochondrial dans le muscle squelettique chez des patients avec une SLA en utilisant la technique des fibres perméabilisées à la saponine sur des fragments musculaires obtenus par biopsie. Nous avons démontré qu il existe bien une altération progressive de la fonction mitochondriale dans le muscle squelettique dans la SLA au fur et à mesure que la maladie progresse. Néanmoins, cette altération ne semble pas être spécifique de la SLA et pourrait résulter de la dénervation musculaire.La protéine Nogo appartient à la superfamille des protéines associées à la myéline et possède dans sa région c-terminale un domaine spécifique de type réticulon. Le gène Nogo code pour plusieurs isoformes, dont Nogo-A. Des observations récentes ont permis de proposer l'utilisation de Nogo-A dans les biopsies musculaires comme marqueur diagnostique précoce de la SLA. Dans ce travail, nous avons réalisé une étude de l'expression de Nogo-A dans le muscle squelettique de patients avec une atteinte isolée du motoneurone spinal. Nos résultats suggèrent que l'expression de Nogo-A dans le muscle de ces patients est un test prédictif qui permet de déterminer lesquels d'entre eux vont développer une SLA. Nous avons également contribué à un travail qui a montré que l'expression musculaire de Nogo-A dans la SLA était corrélée avec la sévérité de l'état clinique du patient et avec le degré d'atrophie des fibres musculaires.Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by degeneration of motoneurons. ALS is usually a sporadic condition of unknown origin. No specific diagnostic marker of ALS exists. It was recently proposed that mitochondrial abnormalities may be involved in ALS pathophysiology. In this work, we performed a temporal study of mitochondrial function in skeletal muscle in patients with ALS using the skinned fiber technique. We demonstrated that mitochondrial function was progressively altered in skeletal muscle in ALS as the disease develops. However, this alteration may not be specific of ALS and may simply be the result of denervation.Nogo is a reticulon-type protein and a member of the myelin-associated proteins superfamily. The Nogo gene encodes several isoforms of the protein, including Nogo-A. Recent observations suggest that Nogo-A expression in skeletal muscle may be used as a diagnostic marker of ALS. In this work, we performed a study of Nogo-A expression in skeletal muscle of patients with lower motor neuron disease. Our results suggest that Nogo-A expression in skeletal muscle of these patients may predict which ones will eventually develop ALS. We also contributed to a study demonstrating that the expression of Nogo-A in skeletal muscle in ALS was correlated with the severity of the disease and with muscle fiber atrophy

Skeletal Muscle in Motor Neuron Diseases: Therapeutic Target and Delivery Route for Potential Treatments.

International audienceLower motor neuron (LMN) degeneration occurs in several diseases that affect patients from neonates to elderly and can either be genetically transmitted or occur sporadically. Among diseases involving LMN degeneration, spinal muscular atrophy (SMA) and spinal bulbar muscular atrophy (Kennedy's disease, SBMA) are pure genetic diseases linked to loss of the SMN gene (SMA) or expansion of a polyglutamine tract in the androgen receptor gene (SBMA) while amyotrophic lateral sclerosis (ALS) can either be of genetic origin or occur sporadically. In this review, our aim is to put forward the hypothesis that muscle fiber atrophy and weakness might not be a simple collateral damage of LMN degeneration, but instead that muscle fibers may be the site of crucial pathogenic events in these diseases. In SMA, the SMN gene was shown to be required for muscle structure and strength as well as for neuromuscular junction formation, and a subset of SMA patients develop myopathic pathology. In SBMA, the occurence of myopathic histopathology in patients and animal models, along with neuromuscular phenotype of animal models expressing the androgen receptor in muscle only has lead to the proposal that SBMA may indeed be a muscle disease. Lastly, in ALS, at least part of the phenotype might be explained by pathogenic events occuring in skeletal muscle. Apart from its potential pathogenic role, skeletal muscle pathophysiological events might be a target for treatments and/or be a preferential route for targeting motor neurons