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Background Facioscapulohumeral dystrophy (FSHD) is caused by mutations leading to the aberrant expression of the DUX4 transcription factor in muscles. DUX4 was proposed to induce cell death, but the involvement of different death pathways is still discussed. A possible pro‐apoptotic role of DUX4 was proposed, but as FSHD muscles are characterized by necrosis and inflammatory infiltrates, non‐apoptotic pathways may be also involved. Methods We explored DUX4‐mediated cell death by focusing on the role of one regulated necrosis pathway called necroptosis, which is regulated by RIPK3. We investigated the effect of necroptosis on cell death in vitro and in vivo experiments using RIPK3 inhibitors and a RIPK3‐deficient transgenic mouse model. Results We showed in vitro that DUX4 expression causes a caspase‐independent and RIPK3‐mediated cell death in both myoblasts and myotubes. In vivo, RIPK3‐deficient animals present improved body and muscle weights, a reduction of the aberrant activation of the DUX4 network genes, and an improvement of muscle histology. Conclusions These results provide evidence for a role of RIPK3 in DUX4‐mediated cell death and open new avenues of research.

To assess in a group of ultrasound operators of various levels of experience the predictive value of systematic quality scoring to assess estimated fetal weight (EFW) validity.Screenshots, sonographer experience, and neonate birth weight were collected for 131 ultrasound examinations in the 7 days before birth. The difference (EFW error) between projected birth weight (EFW + [30 g × interval in days to birth]) and actual birth weight was then assessed (absolute value). Three senior sonographers rated all the screenshots (International Society of Ultrasound in Obstetrics and Gynecology 16-point score for image quality) and interobserver reproducibility was assessed concomitantly. The impact of the score on EFW accuracy was then assessed (univariate analysis). Receiver operating characteristic curves allowed us to assess the score's positive predictive value (PPV) for accurate EFW.Mean birth weight was 2998 ± 954 g and mean EFW error was 8.6% ± 7.1%. Both the sonographer's experience and score significantly impacted the EFW error (P 0.05). The PPVs of systematic image scores for identifying an EFW error greater than 10% and greater than 15% were appropriate for clinical use (areas under the curve 0.61 and 0.70, respectively). Score reproducibility was modest.Low image scores and limited ultrasound expertise are associated with an increased risk of inaccurate EFW.

Facioscapulohumeral muscular dystrophy (FSHD) is a common muscle dystrophy typically affecting patients within their second decade. Patients initially exhibit asymmetric facial and humeral muscle damage, followed by lower body muscle involvement. FSHD is associated with a derepression of DUX4 gene encoded by the D4Z4 macrosatellite located on the subtelomeric part of chromosome 4. DUX4 is a highly regulated transcription factor and its expression in skeletal muscle contributes to multiple cellular toxicities and pathologies ultimately leading to muscle weakness and atrophy. Since the discovery of the FSHD candidate gene DUX4, many cell and animal models have been designed for therapeutic approaches and clinical trials. Today there is no treatment available for FSHD patients and therapeutic strategies targeting DUX4 toxicity in skeletal muscle are being actively investigated. In this review, we will discuss different research areas that are currently being considered to alter DUX4 expression and toxicity in muscle tissue and the cell and animal models designed to date.

Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only ~20% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways.

Facioscapulohumeral dystrophy (FSHD) is the most frequent muscular disease in adults. FSHD is characterized by a weakness and atrophy of a specific set of muscles located in the face, the shoulder, and the upper arms. FSHD patients may present different genetic defects, but they all present epigenetic alterations of the D4Z4 array located on the subtelomeric part of chromosome 4, leading to chromatin relaxation and, ultimately, to the aberrant expression of one gene called DUX4. Once expressed, DUX4 triggers a cascade of deleterious events, eventually leading to muscle dysfunction and cell death. Here, we review studies on DUX4 expression in skeletal muscle to determine the genetic/epigenetic factors and regulatory proteins governing DUX4 expression, with particular attention to the different transcripts and their very low expression in muscle.

Intercellular communication between neurons and their surrounding cells occurs through the secretion of soluble molecules or release of vesicles such as exosomes into the extracellular space, participating in brain homeostasis. Under neuro-degenerative conditions associated with ageing, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s or Parkinson’s disease, exosomes are suspected to propagate toxic proteins. The topic of this review is the role of exosomes in ageing conditions and more specifically in ALS. Our current understanding of exosomes and exosome-related mechanisms is first summarized in a general sense, including their biogenesis and secretion, heterogeneity, cellular interaction and intracellular fate. Their role in the Central Nervous System (CNS) and ageing of the neuromotor system is then considered in the context of exosome-induced signaling. The review then focuses on exosomes in age-associated neurodegenerative disease. The role of exosomes in ALS is highlighted, and their use as potential biomarkers to diagnose and prognose ALS is presented. The therapeutic implications of exosomes for ALS are considered, whether as delivery vehicles, neurotoxic targets or as corrective drugs in and of themselves. A diverse set of mechanisms underpin the functional roles, both confirmed and potential, of exosomes, generally in ageing and specifically in motor neurone disease. Aspects of their contents, biogenesis, uptake and modifications offer many plausible routes towards the development of novel biomarkers and therapeutics.

Aging is associated with both muscle weakness and a loss of muscle mass, contributing towards overall frailty in the elderly. Aging skeletal muscle is also characterised by a decreasing efficiency in repair and regeneration, together with a decline in the number of adult stem cells. Commensurate with this are general changes in whole body endocrine signalling, in local muscle secretory environment, as well as in intrinsic properties of the stem cells themselves. The present review discusses the various mechanisms that may be implicated in these age-associated changes, focusing on aspects of cell-cell communication and long-distance signalling factors, such as levels of circulating growth hormone, IL-6, IGF1, sex hormones, and inflammatory cytokines. Changes in the local environment are also discussed, implicating IL-6, IL-4, FGF-2, as well as other myokines, and processes that lead to thickening of the extra-cellular matrix. These factors, involved primarily in communication, can also modulate the intrinsic properties of muscle stem cells, including reduced DNA accessibility and repression of specific genes by methylation. Finally we discuss the decrease in the stem cell pool, particularly the failure of elderly myoblasts to re-quiesce after activation, and the consequences of all these changes on general muscle homeostasis.