The ER-Bound RING Finger Protein 5 (RNF5/RMA1) Causes Degenerative Myopathy in Transgenic Mice and Is Deregulated in Inclusion Body Myositis

Growing evidence supports the importance of ubiquitin ligases in the pathogenesis of muscular disorders, although underlying mechanisms remain largely elusive. Here we show that the expression of RNF5 (aka RMA1), an ER-anchored RING finger E3 ligase implicated in muscle organization and in recognition and processing of malfolded proteins, is elevated and mislocalized to cytoplasmic aggregates in biopsies from patients suffering from sporadic-Inclusion Body Myositis (sIBM). Consistent with these findings, an animal model for hereditary IBM (hIBM), but not their control littermates, revealed deregulated expression of RNF5. Further studies for the role of RNF5 in the pathogenesis of s-IBM and more generally in muscle physiology were performed using RNF5 transgenic and KO animals. Transgenic mice carrying inducible expression of RNF5, under control of β-actin or muscle specific promoter, exhibit an early onset of muscle wasting, muscle degeneration and extensive fiber regeneration. Prolonged expression of RNF5 in the muscle also results in the formation of fibers containing congophilic material, blue-rimmed vacuoles and inclusion bodies. These phenotypes were associated with altered expression and activity of ER chaperones, characteristic of myodegenerative diseases such as s-IBM. Conversely, muscle regeneration and induction of ER stress markers were delayed in RNF5 KO mice subjected to cardiotoxin treatment. While supporting a role for RNF5 Tg mice as model for s-IBM, our study also establishes the importance of RNF5 in muscle physiology and its deregulation in ER stress associated muscular disorders

Vessel-associated stem cells from skeletal muscle: From biology to future uses in cell therapy

Over the last years, the existence of different stem cells with myogenic potential has been widely investigated. Besides the classical skeletal muscle progenitors represented by satellite cells, numerous multipotent and embryologically unrelated progenitors with a potential role in muscle differentiation and repair have been identified. In order to conceive a therapeutic approach for degenerative muscle disorders, it is of primary importance to identify an ideal stem cell endowed with all the features for a possible use in vivo. Among all emerging populations, vessel-associated stem cells are a novel and promising class of multipotent progenitors of mesodermal origin and with high myogenic potential which seem to best fit all the requirements for a possible cell therapy. In vitro and in viv

Congenital Left Ventricular Diverticulum: A Rare Cause of Recurrent Juvenile Cryptogenic Stroke

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Novel immunolocalization of alpha-synuclein in human muscle of inclusion-body myositis, regenerating and necrotic muscle fibers, and at neuromuscular junctions

Alpha-synuclein (alpha-syn) is an important component of neuronal and glial inclusions in brains of patients with several neurodegenerative disorders. Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease of older patients. Its muscle phenotype shows several similarities with Alzheimer disease brain. A distinct feature of s-IBM pathology is specific vacuolar degeneration of muscle fibers characterized by intracellular amyloid inclusions formed by both amyloid-beta (Abeta) and paired-helical filaments composed of phosphorylated tau. We immunostained alpha-syn in muscle biopsies of s-IBM, disease-control, and normal patients. Approximately 60% of Abeta-positive vacuolated muscle fibers (VMF) contained well-defined inclusions immunoreactive with antibodies against alpha-syn. In those fibers. alpha-syn co-localized with Abeta, both by light microscopy, and ultrastructurally. Paired-helical filaments did not contain alpha-syn immunoreactivity. In all muscle biopsies, alpha-syn was strongly immunoreactive at the postsynaptic region of the neuromuscular junctions. alpha-syn immunoreactivity also occurred diffusely in regenerating and necrotic muscle fibers. In cultured human muscle fibers, alpha-syn and its mRNA were expressed by immunocytochemistry, immunoblots, and Northern blots. Our study provides the first demonstration that alpha-syn participates in normal and pathologic processes of human muscle. Therefore, its function is not exclusive to the brain and neurodegenerative diseases

Hereditary inclusion-body myopathy: clues on pathogenesis and possible therapy

Hereditary inclusion-body myopathy (h-IBM), or distal myopathy with rimmed vacuoles (DMRV), is an autosomal recessive disorder with onset in early adult life and a progressive course leading to severe disability. h-IBM/DMRV is due to mutations of a gene (GNE) that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. Despite the identification of the causative gene defect, it has not been unambiguously clarified how GNE gene mutations impair muscle metabolism. Although numerous studies have indicated a key role of hyposialylation of glycoproteins in h-IBM/DMRV pathogenesis, others have demonstrated new and unpredicted functions of the GNE gene, outside the sialic acid biosynthetic pathway, that may also be relevant. This review illustrates the clinical and pathologic characteristics of h-IBM/DMRV and the main clues available to date concerning the possible pathogenic mechanisms and therapeutic perspectives of this disorde

Large vessel stroke and isolated thrombocytopenia as presenting features of thrombotic thrombocytopenic purpura

Background: Seizures are a common complication of cerebral venous thrombosis. In this study, we intended to define clinical and neuroradiological factors associated with early and late seizures and predictors for seizure recurrence. Methods: The database of our high-volume tertiary stroke center was screened for patients diagnosed with cerebral venous thrombosis between April 2006 and July 2021. Demographics, clinical, imaging, and instrumental data were collected. Results: Out of a total of 80 patients, 30 had seizures, either within the first week after onset (22 patients) or after (8 patients). Speech impairment and intracerebral bleeding were statistically associated with seizures in univariate analysis, but in a logistic regression model, only brain damage with hemorrhagic infarct and/or presence of brain hematoma [OR 6.051; 95% CI 1.881−19.468] (p = 0.003) were predicting factors for seizures. Late seizures were significantly more frequent in younger age [OR 0.864; 95% CI 0.763−0.978] (p = 0.020). Early seizures resulted as protective factors for recurrence; an altered state of consciousness at baseline and late seizures resulted as predictive factors for relapses (0.0% vs. 81.0%, p = 0.005, and 100.0% vs. 19.0%, p < 0.005, respectively). Conclusions: Our study confirms brain bleeding as the strongest risk factor for seizures after cerebral venous thrombosis. Recurrence is unusual after early seizures, while the presence of late seizures seems to raise the risk of recurrence

Autonomic Dysfunction during Acute SARS-CoV-2 Infection: A Systematic Review

Although autonomic dysfunction (AD) after the recovery from Coronavirus disease 2019 (COVID-19) has been thoroughly described, few data are available regarding the involvement of the autonomic nervous system (ANS) during the acute phase of SARS-CoV-2 infection. The primary aim of this review was to summarize current knowledge regarding the AD occurring during acute COVID-19. Secondarily, we aimed to clarify the prognostic value of ANS involvement and the role of autonomic parameters in predicting SARS-CoV-2 infection. According to the PRISMA guidelines, we performed a systematic review across Scopus and PubMed databases, resulting in 1585 records. The records check and the analysis of included reports’ references allowed us to include 22 articles. The studies were widely heterogeneous for study population, dysautonomia assessment, and COVID-19 severity. Heart rate variability was the tool most frequently chosen to analyze autonomic parameters, followed by automated pupillometry. Most studies found ANS involvement during acute COVID-19, and AD was often related to a worse outcome. Further studies are needed to clarify the role of autonomic parameters in predicting SARS-CoV-2 infection. The evidence emerging from this review suggests that a complex autonomic nervous system imbalance is a prominent feature of acute COVID-19, often leading to a poor prognosis

Pharmacological rescue of the dystrophin-glycoprotein complex in Duchenne and Becker skeletal muscle explants by proteasome inhibitor treatment

In this report, we have developed a novel method to identify compounds that rescue the dystrophin-glycoprotein complex (DGC) in patients with Duchenne or Becker muscular dystrophy. Briefly, freshly isolated skeletal muscle biopsies (termed skeletal muscle explants) from patients with Duchenne or Becker muscular dystrophy were maintained under defined cell culture conditions for a 24-h period in the absence or presence of a specific candidate compound. Using this approach, we have demonstrated that treatment with a well-characterized proteasome inhibitor, MG-132, is sufficient to rescue the expression of dystrophin, beta-dystroglycan, and alpha-sarcoglycan in skeletal muscle explants from patients with Duchenne or Becker muscular dystrophy. These data are consistent with our previous findings regarding systemic treatment with MG-132 in a dystrophin-deficient mdx mouse model (Bonuccelli G, Sotgia F, Schubert W, Park D, Frank PG, Woodman SE, Insabato L, Cammer M, Minetti C, and Lisanti MP. Am J Pathol 163: 1663-1675, 2003). Our present results may have important new implications for the possible pharmacological treatment of Duchenne or Becker muscular dystrophy in human