Therapeutic Targets in Amyotrophic Lateral Sclerosis: Focus on Ion Channels and Skeletal Muscle

Amyotrophic Lateral Sclerosis is a neurodegenerative disease caused by progressive loss of motor neurons, which severely compromises skeletal muscle function. Evidence shows that muscle may act as a molecular powerhouse, whose final signals generate in patients a progressive loss of voluntary muscle function and weakness leading to paralysis. This pathology is the result of a complex cascade of events that involves a crosstalk among motor neurons, glia, and muscles, and evolves through the action of converging toxic mechanisms. In fact, mitochondrial dysfunction, which leads to oxidative stress, is one of the mechanisms causing cell death. It is a common denominator for the two existing forms of the disease: sporadic and familial. Other factors include excitotoxicity, inflammation, and protein aggregation. Currently, there are limited cures. The only approved drug for therapy is riluzole, that modestly prolongs survival, with edaravone now waiting for new clinical trial aimed to clarify its efficacy. Thus, there is a need of effective treatments to reverse the damage in this devastating pathology. Many drugs have been already tested in clinical trials and are currently under investigation. This review summarizes the already tested drugs aimed at restoring muscle-nerve cross-talk and on new treatment options targeting this tissue

Working time satisfaction in aging nurses

Satisfaction with working time could represent an index of good balance between work and life and predict satisfactory work ability and endurance of aged workers. This study is aimed at checking whether elderly nurses who were satisfied with working hours had a better work ability index than those unsatisfied, and finding which factors were related to satisfaction of working time with reference to general \u201cwell being\u201d and/or \u201cprivate life\u201d. The study sample consisted of 3,174 female nurses recruited in six European countries within the Nurses\u2019 Early Exit Study. All were rotating shiftworkers (nights included) and 12.95 % were over 45 years of age. A composite questionnaire, including demands at work and in private life, working conditions, individual resources and alternatives to nursing profession, was administered to the participants at baseline and 1 yr later (Time 1). Work ability index (WAI) at time 1 was used as outcome, whereas age groups and satisfaction of working time at baseline were used as predictors, after adjusting for family status and number of children < 7yrs of age. Also \u201csatisfaction with working time\u201d at Time 1 was used as outcome, whereas working hours, job demand, leisure time, influence on planning rotas, family status, number of children, work/family conflicts, sleep at Time 0 were included as potential determinants. Conditional Random Forest analysis was used to evaluate high, moderate or weak importance of these determinants. Nurses satisfied with working time at time 0 showed a higher WAI (time1) than those unsatisfied in all age groups, also over 50. Less work/family conflicts and better quality and quantity sleep turned out to be the best predictors of satisfaction with working time. Consistently, the importance of the other predictors differs when the outcome is \u201csatisfaction with working time\u201d related to general well-being rather than to private life

Statin‐induced myopathy: Translational studies from preclinical to clinical evidence

Statins are the most prescribed and effective drugs to treat cardiovascular diseases (CVD). Nevertheless, these drugs can be responsible for skeletal muscle toxicity which leads to reduced compliance. The discontinuation of therapy increases the incidence of CVD. Thus, it is essential to assess the risk. In fact, many studies have been performed at preclinical and clinical level to investigate pathophysiological mechanisms and clinical implications of statin myotoxicity. Consequently, new toxicological aspects and new biomarkers have arisen. Indeed, these drugs may affect gene transcription and ion transport and contribute to muscle function impairment. Identifying a marker of toxicity is important to prevent or to cure statin induced myopathy while assuring the right therapy for hypercholesterolemia and counteracting CVD. In this review we focused on the mechanisms of muscle damage discovered in preclinical and clinical studies and high-lighted the pathological situations in which statin therapy should be avoided. In this context, preventive or substitutive therapies should also be evaluated

Alteration of stim1/orai1-mediated soce in skeletal muscle: Impact in genetic muscle diseases and beyond

Intracellular Ca2+ ions represent a signaling mediator that plays a critical role in regulating different muscular cellular processes. Ca2+ homeostasis preservation is essential for maintaining skeletal muscle structure and function. Store-operated Ca2+ entry (SOCE), a Ca2+-entry process activated by depletion of intracellular stores contributing to the regulation of various function in many cell types, is pivotal to ensure a proper Ca2+ homeostasis in muscle fibers. It is coordinated by STIM1, the main Ca2+ sensor located in the sarcoplasmic reticulum, and ORAI1 protein, a Ca2+-permeable channel located on transverse tubules. It is commonly accepted that Ca2+ entry via SOCE has the crucial role in short-and long-term muscle function, regulating and adapting many cellular processes including muscle contractility, postnatal development, myofiber phenotype and plasticity. Lack or mutations of STIM1 and/or Orai1 and the consequent SOCE alteration have been associated with serious consequences for muscle function. Importantly, evidence suggests that SOCE alteration can trigger a change of intracellular Ca2+ signaling in skeletal muscle, participating in the pathogenesis of different progressive muscle diseases such as tubular aggregate myopathy, muscular dystrophy, cachexia, and sarcopenia. This review provides a brief overview of the molecular mechanisms underlying STIM1/Orai1-dependent SOCE in skeletal muscle, focusing on how SOCE alteration could contribute to skeletal muscle wasting disorders and on how SOCE components could represent pharmacological targets with high therapeutic potential

Orari di lavoro e sonno nel personale infermieristico impiegato in sistemi di turnazione rapida "23x8" e "2x12"

Obiettivo dello studio \ue8 di verificare, in un campione di 200 infermieri turnisti, l\u2019impatto sul sonno della diversa tipologia di lavoro (\u201cemergenza/urgenza\u201d vs. \u201cdegenza\u201d) nell\u2019ambito dello stesso schema di turno, e di due diversi schemi di turnazione a rotazione rapida (\u201c2x12\u201d e \u201c3x8\u201d), nell\u2019ambito della stessa area di lavoro (\u201cemergenza/urgenza\u201d). Il turno notturno e quello del mattino risultano interferire maggiormente con il sonno, sia in relazione ai due tipi di turno che alle due aree operative considerate. Emerge l\u2019importanza di considerare, nella strutturazione dello schema dei turni, le modalit\ue0 di rotazione tra i turni e il carico di lavoro in relazione alla durata del turno stesso

La percepción de beneficios y de mejora del equilibrio motriz en programas de actividad física en la tercera edad

Nuestro objetivo es estudiar la percepción de los beneficios yde la mejora del equilibrio motriz que tienen los participantes de la terceraedad en un programa de actividad física. Realizamos un enfoque mixedmethods de tipo embedded design de los datos obtenidos de la observaciónsistematizada de los patrones motrices que generan programas dirigidos aeste colectivo; la administración de un test estandarizado de equilibrio engeriatría y un cuestionario validado. Se analizaron 19 sesiones de actividadfísica para obtener los patrones motrices que se desarrollan en dichos programas.Aplicamos el sistema de observación OSMOS_in context, codificadomediante LINCE v.1 y la subsiguiente detección de T-Patterns medianteTHEME v.6, La puntuación del equilibrio motriz, administrando la escalade Tinetti, se obtuvo de los 90 participantes de los programas. Los datosde la percepción de beneficios se han obtenido a partir del cuestionariorealizando un análisis de contenido, mediante el software Atlas-ti v. 6.2.Los T-patterns que hemos obtenido muestran el trabajo específico de estabilidadmotriz de manera conjunta a otras capacidades y habilidades motricesespecíficas, aspectos que se corroboran en la puntuación de la escala deTinetti y que los participantes corroboran y relacionan con una mejoría enla percepción de beneficios tanto físicos como sociales

Consequences of SUR2[A478V] mutation in skeletal muscle of murine model of Cantu syndrome

(1) Background: Cantu syndrome (CS) arises from gain-of-function (GOF) mutations in th

Consequences of SUR2[A478V] mutation in skeletal muscle of murine model of Cantu syndrome

(1) Background: Cantu syndrome (CS) arises from gain-of-function (GOF) mutations in th

Ergogenic effect of bcaas and l-alanine supplementation: Proof-of-concept study in a murine model of physiological exercise

Background: Branched-chain amino acids (BCAAs: leucine, isoleucine, valine) account for 35% of skeletal muscle essential amino acids (AAs). As such, they must be provided in the diet to support peptide synthesis and inhibit protein breakdown. Although substantial evidence has been collected about the potential usefulness of BCAAs in supporting muscle function and structure, dietary supplements containing BCAAs alone may not be effective in controlling muscle protein turnover, due to the rate-limiting bioavailability of other AAs involved in BCAAs metabolism. Methods: We aimed to evaluate the in vivo/ex vivo effects of a 4-week treatment with an oral formulation containing BCAAs alone (2:1:1) on muscle function, structure, and metabolism in a murine model of physiological exercise, which was compared to three modified formulations combining BCAAs with increasing concentrations of L-Alanine (ALA), an AA controlling BCAAs catabolism. Results: A preliminary pharmacokinetic study confirmed the ability of ALA to boost up BCAAs bioavailability. After 4 weeks, mix 2 (BCAAs + 2ALA) had the best protective effect on mice force and fatigability, as well as on muscle morphology and metabolic indices. Conclusion: Our study corroborates the use of BCAAs + ALA to support muscle health during physiological exercise, underlining how the relative BCAAs/ALA ratio is important to control BCAAs distribution