The AMPK allosteric activator MK-8722 improves the histology and spliceopathy in myotonic dystrophy type 1 (DM1) skeletal muscle.

Multiple signaling pathways have been reported to be altered in Myotonic Dystrophy type 1 (DM1) skeletal muscle, contributing to pathogenicity. In particular, previous work established that AMPK signaling, a key sensor of energy metabolism, is repressed in DM1 mouse muscle and that activating AMPK through exercise and/or with pharmacological activators is beneficial for the DM1 muscle phenotype. Here, we explored the effects of a newer, more specific allosteric AMPK activator acting directly on AMPK.

Development and Characterization of an Oncolytic Human Adenovirus-Based Vector Co-Expressing the Adenovirus Death Protein and p14 Fusion-Associated Small Transmembrane Fusogenic Protein.

Human adenovirus (HAdV)-based oncolytic vectors, which are designed to preferentially replicate in and kill cancer cells, have shown modest efficacy in human clinical trials in part due to poor viral distribution throughout the tumor mass. Previously, we showed that expression of the p14 fusion-associated small transmembrane (FAST) fusogenic protein could enhance oncolytic HAdV efficacy and reduce tumor growth rate in a human xenograft mouse model of cancer. We now explore whether co-expression of the adenovirus death protein (ADP) with p14 FAST protein could synergize to further enhance oncolytic vector efficacy.

Tracking myasthenia gravis severity over time: Insights from the French health insurance claims database.

Background And Purpose: Few data are available on the course of myasthenia gravis (MG) regarding disease severity and stability over time in real-world settings. This study used the French National Health Insurance Database (SNDS) to assess markers of disease severity in patients with MG longitudinally.

Methods: All patients with MG-related claims in the SNDS between 2013 and 2020 were identified.

Inflammatory Neuropathy Consortium base (INCbase): a protocol of a global prospective observational cohort study for the development of a prediction model for treatment response in chronic inflammatory demyelinating polyneuropathy.

Background: INCbase is an international, multicenter prospective observational study using a customizable web-based modular registry to study the clinical, biological and electrophysiological variation and boundaries of chronic inflammatory demyelinating polyneuropathy (CIDP). The primary objective of INCbase is to develop and validate a clinical prediction model for treatment response.

Methods: All patients meeting clinical criteria for CIDP can be included in INCbase.

Novel therapies in CIDP.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous but clinically well-described disease within circumscribed parameters. It is immunologically mediated through several poorly understood mechanisms. First-line therapies with steroids, intravenous immunoglobulin (IVIG) or plasma exchange are each effective in about two-thirds of patients.

Effect of Immunosuppression in Risk of Developing Generalized Symptoms in Ocular Myasthenia Gravis: A Retrospective Cohort Study.

Backgrounds And Objectives: Early use of immunosuppression has been suggested to prevent generalization of ocular myasthenia gravis (OMG), but high-quality evidence is limited in this regard. We examined whether treatment with prednisone and other immunosuppressants reduce the risk of generalization in OMG.

Methods: This is a retrospective study of consecutive adults with pure OMG who had a minimum 6 months of follow-up.

Loss of miR-145 promotes remyelination and functional recovery in a model of chronic central demyelination.

Strategies for treating progressive multiple sclerosis (MS) remain limited. Here, we found that miR-145-5p is overabundant uniquely in chronic lesion tissues from secondary progressive MS patients. We induced both acute and chronic demyelination in miR-145 knockout mice to determine its contributions to remyelination failure.

Gestational age at birth influences protein and RNA content in human milk extracellular vesicles.

Human milk extracellular vesicles (HM EVs) are proposed to protect against disease development in infants. This protection could in part be facilitated by the bioactive EV cargo of proteins and RNA. Notably, mothers birth infants of different gestational ages with unique needs, wherein the EV cargo of HM may diverge.

Sex, racial, and ethnic disparities in motor neuron disease: clinical trial enrolment.

Objective: Motor neuron disease (MND) is a group of neurological diseases, the majority being amyotrophic lateral sclerosis (ALS), with varying clinical presentations across demographics. Clinical trial enrollment reflecting global disease burden improves understanding of diverse presentations and aids personalized therapy development. We assessed the sex, racial, and ethnic composition of MND/ALS clinical trial participants relative to global disease burdens.

Cystine/glutamate antiporter xCT controls skeletal muscle glutathione redox, bioenergetics and differentiation.

Cysteine, the rate-controlling amino acid in cellular glutathione synthesis is imported as cystine, by the cystine/glutamate antiporter, xCT, and subsequently reduced to cysteine. As glutathione redox is important in muscle regeneration in aging, we hypothesized that xCT exerts upstream control over skeletal muscle glutathione redox, metabolism and regeneration. Bioinformatic analyses of publicly available datasets revealed that expression levels of xCT and GSH-related genes are inversely correlated with myogenic differentiation genes.

Bioengineering extracellular vesicle cargo for optimal therapeutic efficiency.

Extracellular vesicles (EVs) have the innate ability to carry proteins, lipids, and nucleic acids between cells, and thus these vesicles have gained much attention as potential therapeutic delivery vehicles. Many strategies have been explored to enhance the loading of specific cargoes of interest into EVs, which could result in the delivery of more therapeutic to recipient cells, thus enhancing therapeutic efficacy. In this review, we discuss the natural biogenesis of EVs, the mechanism by which proteins and nucleic acids are selected for inclusion in EVs, and novel methods that have been employed to enhance loading of specific cargoes into EVs.

Pannexin 1 dysregulation in Duchenne muscular dystrophy and its exacerbation of dystrophic features in mdx mice.

Background: Duchenne muscular dystrophy (DMD) is associated with impaired muscle regeneration, progressive muscle weakness, damage, and wasting. While the cause of DMD is an X-linked loss of function mutation in the gene encoding dystrophin, the exact mechanisms that perpetuate the disease progression are unknown. Our laboratory has demonstrated that pannexin 1 (Panx1 in rodents; PANX1 in humans) is critical for the development, strength, and regeneration of male skeletal muscle.

Axonal excitability as an early biomarker of nerve involvement in hereditary transthyretin amyloidosis.

Objectives: The treatment of hereditary transthyretin amyloidosis polyneuropathy (ATTRv-PN) has been revolutionised by genetic therapies, with dramatic improvements in patient outcomes. Whilst the optimal timing of treatment initiation remains unknown, early treatment is desirable. Consequently, the aim of the study was to develop biomarkers of early nerve dysfunction in ATTRv-PN.

SARS-CoV-2 Vaccination and Neuroimmunological Disease: A Review.

Importance: The temporal association between the occurrence of neurological diseases, many autoimmune diseases, and vaccination against SARS-CoV-2 has been topically interesting and remains hotly debated both in the medical literature and the clinic. Given the very low incidences of these events both naturally occurring and in relation to vaccination, it is challenging to determine with certainty whether there is any causative association and most certainly what the pathophysiology of that causation could be.

Observations: Data from international cohorts including millions of vaccinated individuals suggest that there is a probable association between the adenovirus-vectored vaccines and Guillain-Barré syndrome (GBS).

Raised CK and acute kidney injury following intense exercise in three patients with a history of exercise intolerance due to homozygous mutations in SLC2A9.

Acute rhabdomyolysis (AR) leading to acute kidney injury has many underlying etiologies, however, when the primary trigger is exercise, the most usual underlying cause is either a genetic muscle disorder or unaccustomed intense exercise in a healthy individual. Three adult men presented with a history of exercise intolerance and episodes of acute renal impairment following intense exercise, thought to be due to AR in the case of two, and dehydration in one. The baseline serum CK was mildly raised between attacks in all three patients and acutely raised during attacks in two of the three patients.

Long term peripheral AAV9-SMN gene therapy promotes survival in a mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by motor neuron loss and skeletal muscle atrophy. SMA is caused by the loss of the SMN1 gene and low SMN protein levels. Current SMA therapies work by increasing SMN protein in the body.

Optimization of base editors for the functional correction of SMN2 as a treatment for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is caused by mutations in SMN1. SMN2 is a paralogous gene with a C•G-to-T•A transition in exon 7, which causes this exon to be skipped in most SMN2 transcripts, and results in low levels of the protein survival motor neuron (SMN). Here we show, in fibroblasts derived from patients with SMA and in a mouse model of SMA that, irrespective of the mutations in SMN1, adenosine base editors can be optimized to target the SMN2 exon-7 mutation or nearby regulatory elements to restore the normal expression of SMN.

CARM1 drives mitophagy and autophagy flux during fasting-induced skeletal muscle atrophy.

CARM1 (coactivator associated arginine methyltransferase 1) has recently emerged as a powerful regulator of skeletal muscle biology. However, the molecular mechanisms by which the methyltransferase remodels muscle remain to be fully understood. In this study, skeletal muscle-specific knockout (mKO) mice exhibited lower muscle mass with dysregulated macroautophagic/autophagic and atrophic signaling, including depressed AMP-activated protein kinase (AMPK) site-specific phosphorylation of ULK1 (unc-51 like autophagy activating kinase 1; Ser555) and FOXO3 (forkhead box O3; Ser588), as well as MTOR (mechanistic target of rapamycin kinase)-induced inhibition of ULK1 (Ser757), along with AKT/protein kinase B site-specific suppression of FOXO1 (Ser256) and FOXO3 (Ser253).

Emerging and established biomarkers of oculopharyngeal muscular dystrophy.

Oculopharyngeal muscular dystrophy (OPMD) is a rare, primarily autosomal dominant, late onset muscular dystrophy commonly presenting with ptosis, dysphagia, and subsequent weakness of proximal muscles. Although OPMD diagnosis can be confirmed with high confidence by genetic testing, the slow progression of OPMD poses a significant challenge to clinical monitoring and a barrier to assessing the efficacy of treatments during clinical trials. Accordingly, there is a pressing need for more sensitive measures of OPMD progression, particularly those which do not require a muscle biopsy.