BACKGROUND: Long noncoding RNAs (lncRNAs) are noncoding RNA transcripts greater than 200 nucleotides in length and are known to play a role in regulating the transcription of genes involved in vital cellular functions. We hypothesized the disease process in dysferlinopathy is linked to an aberrant expression of lncRNAs and messenger RNAs (mRNAs).
OBJECTIVE: In this study, we compared the lncRNA and mRNA expression profiles between wild-type and dysferlin-deficient murine myoblasts (C2C12 cells).
METHODS: LncRNA and mRNA expression profiling were performed using a microarray. Several lncRNAs with differential expression were validated using quantitative real-time polymerase chain reaction. Gene Ontology (GO) analysis was performed to understand the functional role of the differentially expressed mRNAs. Further bioinformatics analysis was used to explore the potential function, lncRNA-mRNA correlation, and potential targets of the differentially expressed lncRNAs.
RESULTS: We found 3195 lncRNAs and 1966 mRNAs that were differentially expressed. The chromosomal distribution of the differentially expressed lncRNAs and mRNAs was unequal, with chromosome 2 having the highest number of lncRNAs and chromosome 7 having the highest number of mRNAs that were differentially expressed. Pathway analysis of the differentially expressed genes indicated the involvement of several signaling pathways including PI3K-Akt, Hippo, and pathways regulating the pluripotency of stem cells. The differentially expressed genes were also enriched for the GO terms, developmental process and muscle system process. Network analysis identified 8 statistically significant (P<.05) network objects from the upregulated lncRNAs and 3 statistically significant network objects from the downregulated lncRNAs.
CONCLUSIONS: Our results thus far imply that dysferlinopathy is associated with an aberrant expression of multiple lncRNAs, many of which may have a specific function in the disease process. GO terms and network analysis suggest a muscle-specific role for these lncRNAs. To elucidate the specific roles of these abnormally expressed noncoding RNAs, further studies engineering their expression are required.

Pneumatosis cystoides intestinalis (PCI) is a rare disease wherein air accumulates in the intestinal subserosa and submucosa, causing multiple gaseous cysts within the gastrointestinal wall. While PCI has various known risk factors, reports identifying muscular diseases as a factor are scarce. The aim of this study is to elucidate the clinical characteristics of PCI in muscle disease. We present a case series of five cases, including two cases of Duchenne muscular dystrophy (DMD) and three cases of rare congenital myopathies. All cases are of male patients, with poor intestinal peristalsis and constipation, who underwent tube feeding and mechanical ventilation via tracheostomy. They had no signs of severe complications, such as intestinal necrosis, and all of them improved with conservative treatment. Case 1 is a 23-year-old man with DMD who developed cardiopulmonary arrest at the age of 20 years. Pulmonary hemorrhage occurred three months before the incidental detection of PCI in the ascending colon, which resolved with conservative oxygen treatment. Case 2 is a 25-year-old man with DMD who progressed to immobility necessitating tracheostomy at the age of 20 years. He experienced persistent abdominal pain and nausea, and PCI was detected in the cecum and ascending colon. He showed near-complete resolution of PCI after three months of conservative treatment. Case 3 is a six-year-old boy with reducing body myopathy. Constipation was diagnosed at four years of age. He experienced intermittent bloody stools, leading to the incidental detection of PCI at six years of age. After two months of conservative treatment, the PCI resolved with no subsequent recurrence. Case 4 is a 33-year-old man with infantile severe myotubular myopathy. He required mechanical ventilation immediately after birth and later underwent tracheostomy and tube feeding due to complications. At the age of 27 years, PCI was incidentally detected on abdominal CT. He had episodes of remission and worsening for a few years; however, PCI completely resolved after three years. Case 5 is a 27-year-old man with nemaline myopathy. At the age of 14 years, he had persistent bloody stools. After lower gastrointestinal endoscopy, he was diagnosed with PCI with numerous rectal cysts. PCI required no specific therapeutic intervention. There was spontaneous resolution of PCI and bloody stools. Given that PCI lacks specific symptoms and cases with muscular diseases often experience abdominal issues, many cases are liable to be overlooked or misdiagnosed. Cases with muscular diseases complaining of persistent abdominal symptoms should undergo radiographic imaging to rule out PCI.

UNASSIGNED: Plectinopathy-associated disorders are caused by mutations in the PLECTIN (PLEC) gene encoding Plectin protein. PLEC mutations cause a spectrum of diseases defined by varying degrees of signs, mostly with epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) and plectinopathy-related disorder is limb-girdle muscular dystrophy type 2Q (LGMD2Q). Here we report three cases with EBS-MD and LGMD2Q disorders analyzed by exome sequencing followed by mutation confirmation.
UNASSIGNED: A complete clinical examination was done by expert specialists and clinical geneticists in Next Generation Genetic polyclinic, Mashhad, Iran (NGC, years 2020_2021),. Genomic DNA was extracted and evaluated through whole-exome sequencing analysis followed by Sanger sequencing for co-segregation analysis of PLEC candidate variants.
UNASSIGNED: We found three cases with the plectinopathy-related disease, two patients with limb-girdle muscular dystrophy type 2Q (LGMD2Q), and the other affected proband suffers from epidermolysis bullosa simplex combined with muscular dystrophy (EBS-MD) with variable zygosity mutations for PLEC. Motor development disorder and muscular dystrophy symptoms have different age onset in affected individuals. Patients with EBS demonstrated symptoms such as blistering, skin scars, neonatal-onset, and nail dystrophy.
UNASSIGNED: We report plectinopathy-associated disorders to expand clinical phenotypes in different types of PLEC-related diseases. We suppose to design more well-organized research based on comprehensive knowledge about the genetic basis of plectinopathy diseases.

Sarcospan (SSPN) is a 25-kDa transmembrane protein that is broadly expressed at the cell surface of many tissues, including, but not limited to, the myofibers from skeletal and smooth muscles, cardiomyocytes, adipocytes, kidney epithelial cells, and neurons. SSPN is a core component of the dystrophin-glycoprotein complex (DGC) that links the intracellular actin cytoskeleton with the extracellular matrix. It is also associated with integrin α7β1, the predominant integrin expressed in skeletal muscle. As a tetraspanin-like protein with four transmembrane spanning domains, SSPN functions as a scaffold to facilitate protein-protein interactions at the cell membrane. Duchenne muscular dystrophy, Becker muscular dystrophy, and X-linked dilated cardiomyopathy are caused by the loss of dystrophin at the muscle cell surface and a concomitant loss of the entire DGC, including SSPN. SSPN overexpression ameliorates Duchenne muscular dystrophy in the mdx murine model, which supports SSPN being a viable therapeutic target. Other rescue studies support SSPN as a biomarker for the proper assembly and membrane expression of the DGC. Highly specific and robust antibodies to SSPN are needed for basic research on the molecular mechanisms of SSPN rescue, pre-clinical studies, and biomarker evaluations in human samples. The development of SSPN antibodies is challenged by the presence of its four transmembrane domains and limited antigenic epitopes. To address the significant barrier presented by limited commercially available antibodies, we aimed to generate a panel of robust SSPN-specific antibodies that can serve as a resource for the research community. We created antibodies to three SSPN protein epitopes, including the intracellular N- and C-termini as well as the large extracellular loop (LEL) between transmembrane domains 3 and 4. We developed a panel of rabbit antibodies (poly- and monoclonal) against an N-terminal peptide fragment of SSPN. We used several assays to show that the rabbit antibodies recognize mouse SSPN with a high functional affinity and specificity. We developed mouse monoclonal antibodies against the C-terminal peptide and the large extracellular loop of human SSPN. These antibodies are superior to commercially available antibodies and outperform them in various applications, including immunoblotting, indirect immunofluorescence analysis, immunoprecipitation, and an ELISA. These newly developed antibodies will significantly improve the quality and ease of SSPN detection for basic and translational research.

Pathogenic variants in LMNA have been associated with a wide spectrum of muscular conditions: the laminopathies. LMNA-related congenital muscular dystrophy is a laminopathy characterised by the early onset of symptoms and often leads to a fatal outcome at young ages. Children face a heightened risk of malignant arrhythmias. No established paediatric protocols for managing this condition are available. We review published cases and provide insights into disease progression in two twin sisters with LMNA-related muscular dystrophy. Our objective is to propose a cardiac surveillance and management plan tailored specifically for paediatric patients. We present a family of five members, including two twin sisters with LMNA-related muscular dystrophy. A comprehensive neuromuscular and cardiac work-up was performed in all family members. Genetic analysis using massive sequencing technology was performed in both twins. Clinical assessment showed that only the twins showed diagnoses of LMNA-related muscular dystrophy. Follow-up showed an early onset of symptoms and life-threatening arrhythmias, with differing disease progressions despite both twins passing away. Genetic analysis identified a de novo rare missense deleterious variant in the LMNA gene. Other additional rare variants were identified in genes associated with myasthenic syndrome. Early-onset neuromuscular symptoms could be related to a prognosis of worse life-threatening arrhythmias in LMNA related muscular dystrophy. Being a carrier of other rare variants may be a modifying factor in the progression of the phenotype, although further studies are needed. There is a pressing need for specific cardiac recommendations tailored to the paediatric population to mitigate the risk of malignant arrhythmias.

Absence of dystrophin results in muscular weakness, chronic inflammation and cardiomyopathy in Duchenne muscular dystrophy (DMD). Pharmacological corticosteroids are the DMD standard of care; however, they have harsh side effects and unclear molecular benefits. It is uncertain whether signaling by physiological corticosteroids and their receptors plays a modifying role in the natural etiology of DMD. Here, we knocked out the glucocorticoid receptor (GR, encoded by Nr3c1) specifically in myofibers and cardiomyocytes within wild-type and mdx52 mice to dissect its role in muscular dystrophy. Double-knockout mice showed significantly worse phenotypes than mdx52 littermate controls in measures of grip strength, hang time, inflammatory pathology and gene expression. In the heart, GR deletion acted additively with dystrophin loss to exacerbate cardiomyopathy, resulting in enlarged hearts, pathological gene expression and systolic dysfunction, consistent with imbalanced mineralocorticoid signaling. The results show that physiological GR functions provide a protective role during muscular dystrophy, directly contrasting its degenerative role in other disease states. These data provide new insights into corticosteroids in disease pathophysiology and establish a new model to investigate cell-autonomous roles of nuclear receptors and mechanisms of pharmacological corticosteroids.

Three forms of muscular dystrophy-dystroglycanopathies are linked to the ribitol pathway. These include mutations in the isoprenoid synthase domain-containing protein (ISPD), fukutin-related protein (FKRP), and fukutin (FKTN) genes. The aforementioned enzymes are required for generation of the ribitol phosphate linkage in the O-glycan of alpha-dystroglycan. Mild cases of dystroglycanopathy present with slowly progressive muscle weakness, while in severe cases the eyes and brain are also involved. Previous research showed that ribose increased the intracellular concentrations of cytidine diphosphate-ribitol (CDP-ribitol) and had a therapeutic effect. Here, we report the safety and effects of oral ribose supplementation during 6 months in a patient with limb girdle muscular dystrophy type 2I (LGMD2I) due to a homozygous FKRP mutation. Ribose was well tolerated in doses of 9 g or 18 g/day. Supplementation with 18 g of ribose resulted in a decrease of creatine kinase levels of 70%. Moreover, metabolomics showed a significant increase in CDP-ribitol levels with 18 g of ribose supplementation (p < 0.001). Although objective improvement in clinical and patient-reported outcome measures was not observed, the patient reported subjective improvement of muscle strength, fatigue, and pain. This case study indicates that ribose supplementation in patients with dystroglycanopathy is safe and highlights the importance for future studies regarding its potential effects.

Circadian clock and clock-controlled output pathways exert temporal control in diverse aspects of skeletal muscle physiology, including the maintenance of muscle mass, structure, function, and metabolism. They have emerged as significant players in understanding muscle disease etiology and potential therapeutic avenues, particularly in Duchenne muscular dystrophy (DMD). This review examines the intricate interplay between circadian rhythms and muscle physiology, highlighting how disruptions of circadian regulation may contribute to muscle pathophysiology and the specific mechanisms linking circadian clock dysregulation with DMD. Moreover, we discuss recent advancements in chronobiological research that have shed light on the circadian control of muscle function and its relevance to DMD. Understanding clock output pathways involved in muscle mass and function offers novel insights into the pathogenesis of DMD and unveils promising avenues for therapeutic interventions. We further explore potential chronotherapeutic strategies targeting the circadian clock to ameliorate muscle degeneration which may inform drug development efforts for muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive myopathy due to mutations in the dystrophin gene. Diaphragmatic weakness in DMD causes hypoventilation and elevated afterload on the right ventricle (RV). Thus, RV dysfunction in DMD develops early in disease progression. Herein, we deliver a 30-min sustained RV preload/afterload challenge to isolated hearts of wild-type (Wt) and dystrophic (Dmdmdx-4Cv) mice at both young (2-6 month) and middle-age (8-12 month) to test the hypothesis that the dystrophic RV is susceptible to dysfunction with elevated load. Young dystrophic hearts exhibited greater pressure development than wild type under baseline (Langendorff) conditions, but following RV challenge exhibited similar contractile function as wild type. Following the RV challenge, young dystrophic hearts had an increased incidence of premature ventricular contractions (PVCs) compared to wild type. Hearts of middle-aged wild-type and dystrophic mice had similar contractile function during baseline conditions. After RV challenge, hearts of middle-aged dystrophic mice had severe RV dysfunction and arrhythmias, including ventricular tachycardia. Following the RV load challenge, dystrophic hearts had greater lactate dehydrogenase (LDH) release than wild-type mice indicative of damage. Our data indicate age-dependent changes in RV function with load in dystrophin deficiency, highlighting the need to avoid sustained RV load to forestall dysfunction and arrhythmia.

Duchenne muscular dystrophy (DMD) is an X-linked disorder due to a dystrophin mutation and is the leading cause of muscular dystrophy. DMD presents with characteristic systemic effects, including severe muscular atrophy, cardiomyopathy, and ocular manifestations. Performing corneal refractive surgeries in patients with DMD raises concerns regarding patient positioning, risk of cataracts, and other comorbid conditions. Published reports of photorefractive keratectomy, laser-assisted in situ keratomileuses, and small incision lenticule extraction are lacking in this population. Here, we discuss a patient being evaluated for a corneal refractive surgery. This article also discusses the current understanding of DMD, known ocular manifestations, and factors to consider when evaluating a patient for potential corrective vision laser surgery.