Molecular mechanisms and therapeutic strategies for neuromuscular diseases.

Neuromuscular diseases encompass a heterogeneous array of disorders characterized by varying onset ages, clinical presentations, severity, and progression. While these conditions can stem from acquired or inherited causes, this review specifically focuses on disorders arising from genetic abnormalities, excluding metabolic conditions. The pathogenic defect may primarily affect the anterior horn cells, the axonal or myelin component of peripheral nerves, the neuromuscular junction, or skeletal and/or cardiac muscles. While inherited neuromuscular disorders have been historically deemed not treatable, the advent of gene-based and molecular therapies is reshaping the treatment landscape for this group of condition. With the caveat that many products still fail to translate the positive results obtained in pre-clinical models to humans, both the technological development (e.g., implementation of tissue-specific vectors) as well as advances on the knowledge of pathogenetic mechanisms form a collective foundation for potentially curative approaches to these debilitating conditions. This review delineates the current panorama of therapies targeting the most prevalent forms of inherited neuromuscular diseases, emphasizing approved treatments and those already undergoing human testing, offering insights into the state-of-the-art interventions.

Proteomic studies in VWA1-related neuromyopathy allowed new pathophysiological insights and the definition of blood biomarkers.

Bi-allelic variants in VWA1, encoding Von Willebrand Factor A domain containing 1 protein localized to the extracellular matrix (ECM), were linked to a neuromuscular disorder with manifestation in child- or adulthood. Clinical findings indicate a neuromyopathy presenting with muscle weakness. Given that pathophysiological processes are still incompletely understood, and biomarkers are still missing, we aimed to identify blood biomarkers of pathophysiological relevance: white blood cells (WBC) and plasma derived from six VWA1-patients were investigated by proteomics. Four proteins, BET1, HNRNPDL, NEFM and PHGDH, known to be involved in neurological diseases and dysregulated in WBC were further validated by muscle-immunostainings unravelling HNRNPDL as a protein showing differences between VWA1-patients, healthy controls and patients suffering from neurogenic muscular atrophy and BICD2-related neuromyopathy. Immunostaining studies of PHGDH indicate its involvement in apoptotic processes via co-localisation with caspase-3. NEFM showed an increase in cells within the ECM in biopsies of all patients studied. Plasma proteomics unravelled dysregulation of 15 proteins serving as biomarker candidates among which a profound proportion of increased ones (6/11) are mostly related to antioxidative processes and have even partially been described as blood biomarkers for other entities of neuromuscular disorders before. CRP elevated in plasma also showed an increase in the extracellular space of VWA1-mutant muscle. Results of our combined studies for the first time describe pathophysiologically relevant biomarkers for VWA1-related neuromyopathy and suggest that VWA1-patient derived blood might hold the potential to study disease processes of clinical relevance, an important aspect for further preclinical studies.

Deubiquitinases in muscle physiology and disorders.

In vivo, muscle and neuronal cells are post-mitotic, and their function is predominantly regulated by proteostasis, a multilayer molecular process that maintains a delicate balance of protein homeostasis. The ubiquitin-proteasome system (UPS) is a key regulator of proteostasis. A dysfunctional UPS is a hallmark of muscle ageing and is often impacted in neuromuscular disorders (NMDs). Malfunction of the UPS often results in aberrant protein accumulation which can lead to protein aggregation and/or mis-localization affecting its function. Deubiquitinating enzymes (DUBs) are key players in the UPS, controlling protein turnover and maintaining the free ubiquitin pool. Several mutations in DUB encoding genes are linked to human NMDs, such as ATXN3, OTUD7A, UCHL1 and USP14, whilst other NMDs are associated with dysregulation of DUB expression. USP5, USP9X and USP14 are implicated in synaptic transmission and remodeling at the neuromuscular junction. Mice lacking USP19 show increased maintenance of lean muscle mass. In this review, we highlight the involvement of DUBs in muscle physiology and NMDs, particularly in processes affecting muscle regeneration, degeneration and inflammation following muscle injury. DUBs have recently garnered much respect as promising drug targets, and their roles in muscle maturation, regeneration and degeneration may provide the framework for novel therapeutics to treat muscular disorders including NMDs, sarcopenia and cachexia.

CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes.

Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized. Our study revealed that patients with biallelic loss of function in CIAO1 developed proximal and axial muscle weakness, fluctuating creatine kinase elevation, and respiratory insufficiency. In addition, they presented with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, mild normocytic to macrocytic anemia, and gastrointestinal symptoms. Mutational analysis revealed reduced stability of the variants compared with WT CIAO1. Functional assays demonstrated failure of the variants identified in patients to recruit Fe-S recipient proteins, resulting in compromised activities of DNA helicases, polymerases, and repair enzymes that rely on the CIA complex to acquire their Fe-S cofactors. Lentivirus-mediated restoration of CIAO1 expression reversed all patient-derived cellular abnormalities. Our study identifies CIAO1 as a human disease gene and provides insights into the broader implications of the cytosolic Fe-S assembly pathway in human health and disease.

Depletion of Mettl3 in cholinergic neurons causes adult-onset neuromuscular degeneration.

Motor neuron (MN) demise is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Post-transcriptional gene regulation can control RNA's fate, and defects in RNA processing are critical determinants of MN degeneration. N6-methyladenosine (m6A) is a post-transcriptional RNA modification that controls diverse aspects of RNA metabolism. To assess the m6A requirement in MNs, we depleted the m6A methyltransferase-like 3 (METTL3) in cells and mice. METTL3 depletion in embryonic stem cell-derived MNs has profound and selective effects on survival and neurite outgrowth. Mice with cholinergic neuron-specific METTL3 depletion display a progressive decline in motor behavior, accompanied by MN loss and muscle denervation, culminating in paralysis and death. Reader proteins convey m6A effects, and their silencing phenocopies METTL3 depletion. Among the m6A targets, we identified transactive response DNA-binding protein 43 (TDP-43) and discovered that its expression is under epitranscriptomic control. Thus, impaired m6A signaling disrupts MN homeostasis and triggers neurodegeneration conceivably through TDP-43 deregulation.

La cafeína y su efecto ergogénico en el deporte (segunda parte) / Caffeine and its ergogenic effect in sport (second part)

Los efectos de la cafeína sobre el organismo humano han sido estudiados desde hace tiempo y, a día de hoy, ya conocemos gran parte de sus características. En el mundo del deporte, la cafeína es una de las ayudas ergogénicas más populares y empleadas por entrenadores y atletas. Debido a su importancia, en este trabajo nos hemos propuesto el objetivo de analizar los efectos ergogénicos de la cafeína sobre el rendimiento deportivo y todo lo que rodea a esta acción, a través de una revisión de la literatura científica más actual. Hemos seleccionado aquellos estudios que incluyeran sujetos bien entrenados realizando una actividad física que reflejara las actuales prácticas en el deporte, prestando mucha atención a la metodología empleada, esto es la dosis, el momento y la forma de administración de la cafeína, para conseguir alcanzar nuestra meta de constituir una guía actualizada sobre todo lo que rodea a la cafeína como ayuda ergogénica en el deporte. Los resultados obtenidos nos han mostrado una gran variedad de estudios que han investigado acerca de la cafeína y el ejercicio físico siguiendo diferentes metodologías, lo que provoca una imposibilidad de generalizar sobre el asunto. Sin embargo, hemos podido extraer valiosas conclusiones como la clara tendencia hacia la efectividad de la cafeína como ayuda ergogénica en situaciones determinadas, nuevos hallazgos que tienen que ver con el uso de la cafeína en días consecutivos de actividad física, el mejor momento del día para el consumo de la sustancia o la administración estratégica de cafe.na para contrarrestar la falta de sueño, y hacia dónde se dirigen las últimas tendencias en investigación dentro de la materia

The effects of caffeine on the human body have been studied for some time and much is now known about its characteristics. In the sports world, caffeine is one of the most popular ergogenic aids and is widely used by coaches and athletes. Given its importance, in this paper we analyze the ergogenic effects of caffeine on athletic performance and related actions, through a review of the latest scientific literature. We selected studies that included well-trained subjects performing a physical activity that reflects current practices in sport. Close attention was given to the methodology used, including the dose, timing and administration method of the caffeine, with the aim of establishing an updated guide to caffeine as an ergogenic aid in sport. The results show there are a variety of studies that have investigated the effects of caffeine on exercise using different methodologies, making it impossible to reach a general assumption. Nevertheless, we are able to draw valuable conclusions including the clear trend towards the effectiveness of caffeine as an ergogenic aid in certain situations, new findings that deal with the use of caffeine on consecutive days of physical activity, the best time of day to take the substance, the strategic management of caffeine to counteract sleep deprivation, and in what direction the latest research trends in this field are moving

Neuromiopatias / Neuromyopathies

O trabalho visa dar a experiência do autor após 20 anos de funcionamento do ambulatório de miopatias que seria melhor denominado de ambulatório de moléstias da unidade motora. Após mostrarem a atual classificaçäo que usa com 13 itens e 95 afecçöes, o autor refere apenas aquilo no qual tem experiência e sobre o que exista ou näo concordância com a literatura. É chamada atençäo sobretudo para o valor da eletromiografia e da biópsia muscular, exames estes que isoladamente pouco concorrem para o diagnóstico. Näo existe intençäo de descrever o quadro clínico das várias afecçöes mas, apenas colaborar com sua experiência para que especialistas em neurologia possam aproveitar de dados práticos verificados em cerca de 2000 pacientes

Caídas y dependencia. Binomio geriátrico prevenible / Falls and dependency. A presentable association

No disponible

No disponible