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Background/Objectives: Increasing evidence shows an involvement of brain plasticity mechanisms in both motor and central manifestations of neuromuscular disorders (NMDs). These mechanisms could be specifically addressed with neuromodulation or rehabilitation protocols. The aim of this scoping review is to summarise the evidence on plasticity mechanisms' involvement in NMDs to encourage future research. Methods: A scoping review was conducted searching the PubMed and Scopus electronic databases. We selected papers addressing brain plasticity and central nervous system (CNS) studies through non-invasive brain stimulation techniques in myopathies, muscular dystrophies, myositis and spinal muscular atrophy. Results: A total of 49 papers were selected for full-text examination. Regardless of the variety of pathogenetic and clinical characteristics of NMDs, studies show widespread changes in intracortical inhibition mechanisms, as well as disruptions in glutamatergic and GABAergic transmission, resulting in altered brain plasticity. Therapeutic interventions with neurostimulation techniques, despite being conducted only anecdotally or on small samples, show promising results; Conclusions: despite challenges posed by the rarity and heterogeneity of NMDs, recent evidence suggests that synaptic plasticity may play a role in the pathogenesis of various muscular diseases, affecting not only central symptoms but also strength and fatigue. Key questions remain unanswered about the role of plasticity and its potential as a therapeutic target. As disease-modifying therapies advance, understanding CNS involvement in NMDs could lead to more tailored treatments. [ABSTRACT FROM AUTHOR]

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MRI's T2 relaxation time is a valuable biomarker for neuromuscular disorders and muscle dystrophies. One of the hallmarks of these pathologies is the infiltration of adipose tissue and a loss of muscle volume. This leads to a mixture of two signal components, from fat and from water, to appear in each imaged voxel, each having a specific T2 relaxation time. In this proof‐of‐concept work, we present a technique that can separate the signals from water and from fat within each voxel, measure their separate T2 values, and calculate their relative fractions. The echo modulation curve (EMC) algorithm is a dictionary‐based technique that offers accurate and reproducible mapping of T2 relaxation times. We present an extension of the EMC algorithm for estimating subvoxel fat and water fractions, alongside the T2 and proton‐density values of each component. To facilitate data processing, calf and thigh anatomy were automatically segmented using a fully convolutional neural network and FSLeyes software. The preprocessing included creating two signal dictionaries, for water and for fat, using Bloch simulations of the prospective protocol. Postprocessing included voxelwise fitting for two components, by matching the experimental decay curve to a linear combination of the two simulated dictionaries. Subvoxel fat and water fractions and relaxation times were generated and used to calculate a new quantitative biomarker, termed viable muscle index, and reflecting disease severity. This biomarker indicates the fraction of remaining muscle out of the entire muscle region. The results were compared with those using the conventional Dixon technique, showing high agreement (R = 0.98, p < 0.001). It was concluded that the new extension of the EMC algorithm can be used to quantify abnormal fat infiltration as well as identify early inflammatory processes corresponding to elevation in the T2 value of the water (muscle) component. This new ability may improve the diagnostic accuracy of neuromuscular diseases, help stratification of patients according to disease severity, and offer an efficient tool for tracking disease progression. [ABSTRACT FROM AUTHOR]

Over the past centuries, myology as a basic and clinical science has passed through three major stages of development: the classical period, the modern nosographic stage, and the molecular era. The classical period spans the sixteenth century up to the earlier parts of the twentieth century. During this time, several major muscle diseases were clinically and pathologically characterized, including Duchenne muscular dystrophy (DMD), myotonic dystrophy, and facioscapulo-humeral dystrophy, by master clinicians such as Duchenne, Erb, Becker, Steinert, Landouzy, Dejerine, Meryon, and others. These accomplishments laid solid foundations for the following modern era with nosographic classification and the following molecular era. European clinicians and scientists were major contributors to the modern era in the second half of the twentieth century, which is characterized by three major discoveries. First, it was observed that substantial elevation of the serum activity of creatine kinase indicates muscle damage or destruction. Then, the adaptation of modern histo-and cytochemical techniques to the study of muscle biopsies markedly improved the diagnostic accuracy and made possible the identification of new changes and structures. Thirdly, the advent of modern biochemical techniques permitted the identification of various enzyme defects/storage diseases such as Pompe disease, McArdle's disease, and carnitine deficiency states. The molecular era was made possible by the strikingly fast development of molecular biology and its application to muscle diseases. This permitted the identification of gene defects in many inherited diseases, leading to an accurate and specific diagnosis. The growth of international collaboration in Europe was achieved through the exchange of international scientists and collaborative networks. [ABSTRACT FROM AUTHOR]

The vegetal polyphenol curcumin displays beneficial effects against skeletal muscle derangement induced by oxidative stress, disuse or aging. Since oxidative stress and inflammation are involved in the progression of muscle dystrophy, the effects of curcumin administration were investigated in the diaphragm of mdx mice injected intraperitoneally or subcutaneously with curcumin for 4–12–24 weeks. Curcumin treatment independently of the way and duration of administration (i) ameliorated myofiber maturation index without affecting myofiber necrosis, inflammation and degree of fibrosis; (ii) counteracted the decrease in type 2X and 2B fiber percentage; (iii) increased about 30% both twitch and tetanic tensions of diaphragm strips; (iv) reduced myosin nitrotyrosination and tropomyosin oxidation; (v) acted on two opposite nNOS regulators by decreasing active AMP-Kinase and increasing SERCA1 protein levels, the latter effect being detectable also in myotube cultures from mdx satellite cells. Interestingly, increased contractility, decreased myosin nitrotyrosination and SERCA1 upregulation were also detectable in the mdx diaphragm after a 4-week administration of the NOS inhibitor 7-Nitroindazole, and were not improved further by a combined treatment. In conclusion, curcumin has beneficial effects on the dystrophic muscle, mechanistically acting for the containment of a deregulated nNOS activity. [ABSTRACT FROM AUTHOR]

Objective: In muscular dystrophies (MD) patients with end-stage heart failure (HF), continuous flow left ventricular assist device (cf-LVAD) therapy is still controversial due to a progressive nature of MD-associated muscle weakness. Methods: All the MD patients who had cf- VAD implants between March 2013 and August 2019 in our hospital were retrospectively studied. Study end points were death, major LVAD-associated complications or respiratory dysfunction caused by muscular weakness. Results: A total of 11 MD patients (Becker type: n = 6; Emery–Dreifuss Myodystrophy: n = 2; Fukuyama subtype: n = 1; Limb-girdle 1B: n = 2) were enrolled. Demographics: median age 41 years (IQR; 29–47); median Japanese Registry for Mechanically Assisted Circulatory Support: level 3 (2–3); a median interval between MD diagnosis and LVAD implantation 9 years (6–18). The pulmonary function test at LVAD implantation showed a median of %VC; 62% (45–82), FEV1%, 82% (81–88). Survival to discharge was 100% without pulmonary complication and early VAD-related complications. During a median follow-up of 38 months (27–53), re-admissions were needed due to device infection (n = 2), cerebrovascular accidents (disabling, n = 2 and non-disabling, n = 2), ventricular tachycardia (n = 4), and right HF (n = 3), respectively. 7 patients received successful heart transplant after a median waiting time of 44 months (34–61); 3 patients are still on the waiting list (waiting time: 21, 38, and 39 months). One patient died of right HF 15 months after VAD implantation. No one had overt pulmonary dysfunction during LVAD support. Conclusion: In selected MD patients with end-stage HF, cf-LVAD therapy is a viable therapeutic option as bridge to heart transplant. [ABSTRACT FROM AUTHOR]

Over the past centuries, myology as a basic and clinical science has passed through three major stages of development: the classical period, the modern nosographic stage, and the molecular era. The classical period spans the sixteenth century up to the earlier parts of the twentieth century. During this time, several major muscle diseases were clinically and pathologically characterized, including Duchenne muscular dystrophy (DMD), myotonic dystrophy, and facio-scapulo-humeral dystrophy, by master clinicians such as Duchenne, Erb, Becker, Steinert, Landouzy, Dejerine, Meryon, and others. These accomplishments laid solid foundations for the following modern era with nosographic classification and the following molecular era. European clinicians and scientists were major contributors to the modern era in the second half of the twentieth century, which is characterized by three major discoveries. First, it was observed that substantial elevation of the serum activity of creatine kinase indicates muscle damage or destruction. Then, the adaptation of modern histo-and cytochemical techniques to the study of muscle biopsies markedly improved the diagnostic accuracy and made possible the identification of new changes and structures. Thirdly, the advent of modern biochemical techniques permitted the identification of various enzyme defects/storage diseases such as Pompe disease, McArdle's disease, and carnitine deficiency states. The molecular era was made possible by the strikingly fast development of molecular biology and its application to muscle diseases. This permitted the identification of gene defects in many inherited diseases, leading to an accurate and specific diagnosis. The growth of international collaboration in Europe was achieved through the exchange of international scientists and collaborative networks.

Biallelic pathogenic variants in the genes encoding the dolichol‐phosphate mannose synthase subunits (DPM) which produce mannosyl donors for glycosylphosphatidylinositols, N‐glycan and protein O‐ and C‐mannosylation, are rare causes of congenital disorders of glycosylation. Pathogenic variants in DPM1 and DPM2 are associated with muscle–eye–brain (MEB) disease, whereas DPM3 variants have mostly been reported in patients with isolated muscle disease—dystroglycanopathy. Thus far, only one affected individual with compound heterozygous DPM3 variants presenting with myopathy, mild intellectual disability, seizures, and nonspecific white matter abnormalities (WMA) around the lateral ventricles has been described. Here we present five affected individuals from four unrelated families with global developmental delay/intellectual disability ranging from mild to severe, microcephaly, seizures, WMA, muscle weakness and variable cardiomyopathy. Exome sequencing of the probands revealed an ultra‐rare homozygous pathogenic missense DPM3 variant NM_018973.4:c.221A>G, p.(Tyr74Cys) which segregated with the phenotype in all families. Haplotype analysis indicated that the variant arose independently in three families. Functional analysis did not reveal any alteration in the N‐glycosylation pathway caused by the variant; however, this does not exclude its pathogenicity in the function of the DPM complex and related cellular pathways. This report provides supporting evidence that, besides DPM1 and DPM2, defects in DPM3 can also lead to a muscle and brain phenotype. [ABSTRACT FROM AUTHOR]

• Clinical epidemiology of inherited myopathies in sub-Saharan Africa (SSA) is unknown. • We report a case series with 9 patients from SSA. • All patients had the diagnosis of muscular dystrophy. • The inherited myopathies in this cohort were the same found in western world. The clinical epidemiology of inherited myopathies in sub-Saharan Africa (SSA) is unknown but likely underdiagnosed due to problems of scientific research and social issues. We report a case series of patients born in SSA, evacuated to Portugal through an international health protocol and seen at a single neuromuscular disorders centre, between January/2004 and August/2021. We identified 9 patients (5 males), 35.6 ± 19.3 years-old (10–64), from Cape Verde (n = 4), Angola (n = 2), Sao Tome and Principe (n = 2) and Guinea-Bissau (n = 1), with a delay in diagnosis of 19.7 ± 14.3 years. Seven patients (77.8 %) had positive family history. Most patients had significant morbidity, requiring wheelchair (55.6 %), and nocturnal non-invasive ventilation (55.6 %). The diagnosis included Bethlem myopathy (n = 2), Duchenne muscular dystrophy (n = 2), Emery-Dreifuss muscular dystrophy (n = 1), LGMDR1 (n = 2), LGMDR2 (n = 1), and type-1 myotonic dystrophy (n = 1). Genetic testing was remarkable for 3 mutations previously not described. Despite the small sample, the spectrum of hereditary myopathies in our cohort is like western studies. Further studies are needed to better understand the epidemiology of muscle diseases in SSA. [ABSTRACT FROM AUTHOR]

Introduction/aim: The most common limb girdle muscular dystrophy (LGMD) worldwide is LGMD type R1 (LGMDR1). The aim of this study was to correlate the MRI findings with functional scores and to describe the whole-body MRI (WBMRI) pattern in a LGMDR1 Brazilian cohort.Methods: LGMDR1 patients under follow-up in three centers were referred for the study. Clinical data were collected and a functional evaluation was performed, consisting of Gardner-Medwin and Walton (GMW) and Brooke scales. All patients underwent a WBMRI study (1.5T) with axial T1 and STIR images. Fifty-one muscles were semiquantitatively assessed regarding fatty infiltration and muscle edema.Results: The study group consisted of 18 patients. The highest fatty infiltration scores involved the serratus anterior, biceps femoris long head, adductor magnus, and lumbar erector spinae. There was a latero-medial and caudo-cranial descending gradient of involvement of the paravertebral muscles, with erector spinae being significantly more affected than the transversospinalis muscles (p < 0.05). A striped appearance that has been dubbed the "pseudocollagen sign" was present in 72% of the patients. There was a positive correlation between the MRI score and GMW (Rho:0.83) and Brooke (Rho:0.53) scores.Discussion: WBMRI in LGMDR1 allows a global patient evaluation including involvement of the paraspinal muscles, usually an underestimated feature in the clinical and imaging study of myopathies. Knowledge of the WBMRI pattern of LGMDR1 involvement can be useful in the diagnostic approach and in future studies to identify the best target muscles to serve as outcome measures in clinical trials. [ABSTRACT FROM AUTHOR]

Introduction/Aims: With current and anticipated disease‐modifying treatments, including gene therapy, an early diagnosis for Duchenne muscular dystrophy (DMD) is crucial to assure maximum benefit. In 2009, a study from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) showed an average diagnosis age of 5 years among males with DMD born from January 1, 1982 to December 31, 2000. Initiatives were implemented by the US Centers for Disease Control and Prevention (CDC) and patient organizations to reduce time to diagnosis. We conducted a follow‐up study in a surveillance cohort born after January 1, 2000 to determine whether there has been an improvement in time to diagnosis. Methods: We assessed the age of diagnosis among males with DMD born from January 1, 2000 to December 31, 2015 using data collected by six US MD STARnet surveillance sites (Colorado, Iowa, western New York State, the Piedmont region of North Carolina, South Carolina, and Utah). The analytic cohort included 221 males with definite or probable DMD diagnosis without a documented family history. We computed frequency count and percentage for categorical variables, and mean, median, and standard deviation (SD) for continuous variables. Results: The mean [median] ages in years of diagnostic milestones were: first signs, 2.7 [2.0]; first creatine kinase (CK), 4.6 [4.6]; DNA/muscle biopsy testing, 4.9 [4.8]; and time from first signs to diagnostic confirmation, 2.2 [1.4]. Discussion: The time interval between first signs of DMD and diagnosis remains unchanged at 2.2 years. This results in lost opportunities for timely genetic counseling, implementation of standards of care, initiation of glucocorticoids, and participation in clinical trials. See Editorial on pages 116‐117 in this issue [ABSTRACT FROM AUTHOR]

Popeye domain containing protein 1 (POPDC1) is a highly conserved transmembrane protein essential for striated muscle function and homeostasis. Pathogenic variants in the gene encoding POPDC1 (BVES, Blood vessel epicardial substance) are causative for limb-girdle muscular dystrophy (LGMDR25), associated with cardiac arrhythmia. We report on four affected children (age 7–19 years) from two consanguineous families with two novel pathogenic variants in BVES c.457C>T(p.Q153X) and c.578T>G (p.I193S). Detailed analyses were performed on muscle biopsies from an affected patient of each family including immunofluorescence, electron microscopy and proteomic profiling. Cardiac abnormalities were present in all patients and serum creatine kinase (CK) values were variably elevated despite lack of overt muscle weakness. Detailed histological analysis of skeletal muscle, however indicated a myopathy with reduced sarcolemmal expression of POPDC1 accompanied by altered sarcolemmal and sarcoplasmatic dysferlin and Xin/XIRP1 abundance. At the electron microscopic level, the muscle fiber membrane was focally disrupted. The proteomic signature showed statistically significant dysregulation of 191 proteins of which 173 were increased and 18 were decreased. Gene ontology-term analysis of affected biological processes revealed - among others - perturbation of muscle fibril assembly, myofilament sliding, and contraction as well as transition between fast and slow fibers. In conclusion, these findings demonstrate that the phenotype of LGMDR25 is highly variable and also includes younger children with conduction abnormalities, no apparent muscular problems, and only mildly elevated CK values. Biochemical studies suggest that BVES mutations causing loss of functional POPDC1 can impede striated muscle function by several mechanisms. • Two novel mutations in BVES are associated with an early onset of LGMD25. • Loss of POPDC1 is accompanied by altered sarcolemmal and sarcoplasmatic dysferlin and Xin/XIRP1. • In children with cardiac symptoms, a neuromuscular disorder should be ruled out. • Expression of POPDC1 in cardiac muscle highlights the cardio-skeletal link in LGMD. [ABSTRACT FROM AUTHOR]

The Neuromuscular Junction (NMJ) is a chemical synapse localized between the terminal branches of the spinal motor neurons and myofibers. In the past two decades coculture systems to generate the NMJ in culture are developed to address concerns about animal models, despite the complexity of its highly specialized structure makes the in vitro modeling a challenging task. Microfluidics, unlike mass cocultures, allow spatial and temporal control over different microenvironment by manipulating either neural cells or muscle cell populations independently. Therefore, exploiting an organ‐on‐a‐chip approach, the aim is to obtain a reliable and predictive in vitro human model of NMJ in physiological and pathological conditions, to investigate the occurrence of synapse detriment in α‐sarcoglycanopathy, a subtype of limb‐girdle muscular dystrophy. For this purpose, motor neurons derived from human induced pluripotent stem cells (hiPSCs) and either healthy or α‐sarcoglycan mutant human myogenic progenitors are seeded in two separated chambers of a microfluidic device. Differentiated myotubes and hiPSCs‐derived motor neurons on‐chip are able to establish points of interaction where pre‐ and postsynaptic structures colocalize. Moreover, the attraction of motor neurons axons by muscle fibers and the NMJ maturation appear to be affected by the muscular compartment, being impaired by the dystrophic cellular component. [ABSTRACT FROM AUTHOR]

The vegetal polyphenol curcumin displays beneficial effects against skeletal muscle derangement induced by oxidative stress, disuse or aging. Since oxidative stress and inflammation are involved in the progression of muscle dystrophy, the effects of curcumin administration were investigated in the diaphragm of mdx mice injected intraperitoneally or subcutaneously with curcumin for 4–12–24 weeks. Curcumin treatment independently of the way and duration of administration (i) ameliorated myofiber maturation index without affecting myofiber necrosis, inflammation and degree of fibrosis; (ii) counteracted the decrease in type 2X and 2B fiber percentage; (iii) increased about 30% both twitch and tetanic tensions of diaphragm strips; (iv) reduced myosin nitrotyrosination and tropomyosin oxidation; (v) acted on two opposite nNOS regulators by decreasing active AMP-Kinase and increasing SERCA1 protein levels, the latter effect being detectable also in myotube cultures from mdx satellite cells. Interestingly, increased contractility, decreased myosin nitrotyrosination and SERCA1 upregulation were also detectable in the mdx diaphragm after a 4-week administration of the NOS inhibitor 7-Nitroindazole, and were not improved further by a combined treatment. In conclusion, curcumin has beneficial effects on the dystrophic muscle, mechanistically acting for the containment of a deregulated nNOS activity.

Limb-girdle muscular dystrophy R12 (LGMD-R12) is caused by two mutations in anoctamin-5 (ANO5). Our aim was to identify genes and pathways that underlie LGMD-R12 and explain differences in the molecular predisposition and susceptibility between three thigh muscles that are severely (semimembranosus), moderately (vastus lateralis) or mildly (rectus femoris) affected in this disease. We performed transcriptomics on these three muscles in 16 male LGMD-R12 patients and 15 age-matched male controls. Our results showed that LGMD-R12 dystrophic muscle is associated with the expression of genes indicative of fibroblast and adipocyte replacement, such as fibroadipogenic progenitors and immune cell infiltration, while muscle protein synthesis and metabolism were downregulated. Muscle degeneration was associated with an increase in genes involved in muscle injury and inflammation, and muscle repair/regeneration. Baseline differences between muscles in healthy individuals indicated that muscles that are the most affected by LGMD-R12 have the lowest expression of transcription factor networks involved in muscle (re)generation and satellite stem cell activation. Instead, they show relative high levels of fetal/embryonic myosins, all together indicating that muscles differ in their baseline regenerative potential. To conclude, we profiled the gene expression landscape in LGMD-R12, identified baseline differences in expression levels between differently affected muscles and characterized disease-associated changes. [ABSTRACT FROM AUTHOR]

Background: Nutritional muscle dystrophy is associated with selenium (Se) deficiency; however, the underlying mechanism remains unclear.Objectives: This study aimed to understand the crosstalk among redox status, energy metabolism, and inflammation in nutritional muscle dystrophy induced by dietary Se deficiency.Methods: Eighteen castrated male pigs (Yorkshire, 45 d old) were fed Se-deficient (Se-D; 0.007 mg Se/kg) or Se-adequate (Se-A; in the form of selenomethionine, 0.3 mg Se/kg) diets for 16 wk. The muscle Se concentrations; antioxidant capacity; and gene expression, transcriptome, global proteome, metabolome, and lipidome profiles were analyzed. The transcriptome, metabolome, and proteome profiles were analyzed with biostatistics, bioinformatics, and pathway enrichment analysis; other data were analyzed with Student's 2-sided t tests.Results: The muscle Se content in the Se-D group was 96% lower than that in the Se-A group (P < 0.05). The activity of glutathione peroxidase (GPX) and thioredoxin reductase (TXNRD) in the Se-D group was 42%-69% lower than that in the Se-A group (P < 0.05). The mRNA levels of 10 selenoprotein genes were 25%-84% lower than those in the Se-A group (P < 0.05). Multi-omics analyses indicated that the levels of 1378 transcripts, 83 proteins, 22 metabolites, and 55 lipid molecules were significantly altered in response to Se deficiency. Se deficiency-induced redox imbalance led to muscle central carbon and lipid metabolism reprogramming, which enhanced the glycolysis pathway and decreased phospholipid synthesis. Inflammation and apoptosis were observed in response to Se deficiency-induced muscle oxidative stress, which may have been associated with extracellular matrix (ECM) remodeling, suppressed focal adhesion and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, and activation of the NF-κB signaling pathway.Conclusions: These results contributed to understanding the crosstalk among redox, energy metabolism, and inflammation in Se deficiency-induced muscle dystrophy in pigs, and may provide intervention targets for muscle disease treatment. [ABSTRACT FROM AUTHOR]

The purpose of this scoping review was to report the effects of vibration therapy, electrical stimulation, and transcranial magnetic stimulation on patients with muscle dystrophies. The outcome measures were muscle strength, body composition, balance, and functional mobility of these patients. We used the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and the Arksey and O'Malley framework. The literature review was conducted on PubMed. We included studies that were written in English, were peer-reviewed, without regard to the publication date, and implemented a form of "vibration therapy" or "electrical stimulation" or "magnetic stimulation" as an intervention program of any duration. Overall, 14 studies were retrieved. Most of the studies applied whole-body vibration (WBV) therapy or electrical stimulation and only one was found that implemented transcranial magnetic stimulation. The interventions were reported but there was a variety in duration or the frequency of the program, as well as in the disease progression of the patients. It seems that WBV, electrical stimulation, and magnetic stimulation have positive outcomes, but these vary depending on the muscle deficits and limitations of the patients with muscle dystrophy. It is recommended that future studies should be conducted in order to determine the ideal prescription of each intervention, so as to be as beneficial as possible., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Venieri et al.)

Exploring Hypotension Treatment Targets in Duchenne Muscular Dystrophy (DMD): This study utilizes snRNA-seq analysis to pinpoint possible treatment targets for hypotension in DMD. We hypothesize that heightened KCNQ5 and RyR2 expression, in particular, contributes to decreased arterial blood pressure in DMD patients (Created in BioRender). [Display omitted] • There is a link between DMD mutations and hypotension in DMD patients. • ScRNA-seq data identified KCNQ5 and RyR2 as candidates influencing hypotension in DMD. • Hypotheses: Inhibiting the KCNQ5 and RyR2 channels might treat hypotension in DMD. • Efficiency, dosage, and limitations of various KCNQ5 and RyR2 inhibitors. Duchenne Muscular Dystrophy (DMD) is marked by genetic mutations occurring in the DMD gene, which is widely expressed in the cardiovascular system. In addition to developing cardiomyopathy, patients with DMD have been reported to be susceptible to the development of symptomatic hypotension, although the mechanisms are unclear. Analysis of single-cell RNA sequencing data has identified potassium voltage-gated channel subfamily Q member 5 (KCNQ5) and possibly ryanodine receptor 2 (RyR2) as potential candidate hypotension genes whose expression is significantly upregulated in the vascular smooth muscle cells of DMD mutant mice. We hypothesize that heightened KCNQ5 and RyR2 expression contributes to decreased arterial blood pressure in patients with DMD. Exploring pharmacological approaches to inhibit the KCNQ5 and RyR2 channels holds promise in managing the systemic hypotension observed in individuals with DMD. This avenue of investigation presents new prospects for improving clinical outcomes for these patients. [ABSTRACT FROM AUTHOR]

Abstract TRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopathy (Bardet-Biedl syndrome type11), suggesting that these domains are involved in distinct processes. Knock-out (T32KO) and knock-in mice carrying the c.1465G > A (p.D489N) involving the NHL domain (T32KI) show alterations in muscle regrowth after atrophy and satellite cells senescence. Here, we present phenotypical description and functional characterization of mutations in the RING, coiled-coil and NHL domains of TRIM32 causing a muscle dystrophy. Reduced levels of TRIM32 protein was observed in all patient muscle studied, regardless of the type of mutation (missense, single amino acid deletion, and frameshift) or the mutated domain. The affected patients presented with variable phenotypes but predominantly proximal weakness. Two patients had symptoms of both muscular dystrophy and Bardet-Biedl syndrome. The muscle magnetic resonance imaging (MRI) pattern is highly variable among patients and families. Primary myoblast culture from these patients demonstrated common findings consistent with reduced proliferation and differentiation, diminished satellite cell pool, accelerated senescence of muscle, and signs of autophagy activation.

Abstract Background Collagen VI-related myopathies are a spectrum of muscular diseases with features of muscle weakness and atrophy, multiple contractures of joints, distal hyperextensibility, severe respiratory dysfunction and cutaneous alterations, attributable to mutations in the COL6A1, COL6A2, and COL6A3 genes. However, no case of collagen VI mutations with hematuria has been reported. We report a 14-year-old boy who had both Bethlem myopathy and recurrent hematuria and who carried a known de novo COL6A1 missense mutation c.877G > A (p.G293R). Case presentation The patient was a 14-year-old boy presenting with muscle weakness from 3 years of age without any family history. Six months before admission, he developed recurrent gross hematuria, three bouts in total, with the presence of blood clots in the urine. Next-generation sequencing of his whole-exome was performed. The result of sequencing revealed a de novo heterozygous G-to-A nucleotide substitution at position 877 in exon 10 of the COL6A1 gene. After treatment, the hematuria healed, but the muscle weakness failed to improve. Conclusions Hematuria in Bethlem myopathy can be caused by COL6 mutations, which may be related to the aberrant connection between collagen VI and collagen IV.

Limb-girdle muscular dystrophy R12 (LGMD-R12) is caused by two mutations in anoctamin-5 (ANO5). Our aim was to identify genes and pathways that underlie LGMD-R12 and explain differences in the molecular predisposition and susceptibility between three thigh muscles that are severely (semimembranosus), moderately (vastus lateralis) or mildly (rectus femoris) affected in this disease. We performed transcriptomics on these three muscles in 16 male LGMD-R12 patients and 15 age-matched male controls. Our results showed that LGMD-R12 dystrophic muscle is associated with the expression of genes indicative of fibroblast and adipocyte replacement, such as fibroadipogenic progenitors and immune cell infiltration, while muscle protein synthesis and metabolism were downregulated. Muscle degeneration was associated with an increase in genes involved in muscle injury and inflammation, and muscle repair/regeneration. Baseline differences between muscles in healthy individuals indicated that muscles that are the most affected by LGMD-R12 have the lowest expression of transcription factor networks involved in muscle (re)generation and satellite stem cell activation. Instead, they show relative high levels of fetal/embryonic myosins, all together indicating that muscles differ in their baseline regenerative potential. To conclude, we profiled the gene expression landscape in LGMD-R12, identified baseline differences in expression levels between differently affected muscles and characterized disease-associated changes.

The dystrophin-glycoprotein complex (DGC) plays a crucial role in maintaining the structural integrity of the plasma membrane and the neuromuscular junction. In this study, we investigated the impact of the deficiency of α-dystrobrevin (αdbn), a component of the DGC, on the homeostasis of intracellular organelles, specifically mitochondria and the sarcoplasmic reticulum (SR). In αdbn deficient muscles, we observed a significant increase in the membrane-bound ATP synthase complex levels, a marker for mitochondria in oxidative muscle fiber types compared to wild-type. Furthermore, examination of muscle fibers deficient in αdbn using electron microscopy revealed profound alterations in the organization of mitochondria and the SR within certain myofibrils of muscle fibers. This included the formation of hyper-branched intermyofibrillar mitochondria with extended connections, an extensive network spanning several myofibrils, and a substantial increase in the number/density of subsarcolemmal mitochondria. Concurrently, in some cases, we observed significant structural alterations in mitochondria, such as cristae loss, fragmentation, swelling, and the formation of vacuoles and inclusions within the mitochondrial matrix cristae. Muscles deficient in αdbn also displayed notable alterations in the morphology of the SR, along with the formation of distinct anomalous concentric SR structures known as whorls. These whorls were prevalent in αdbn-deficient mice but were absent in wild-type muscles. These results suggest a crucial role of the DGC αdbn in regulating intracellular organelles, particularly mitochondria and the SR, within muscle cells. The remodeling of the SR and the formation of whorls may represent a novel mechanism of the unfolded protein response (UPR) in muscle cells., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The muscle is the principal tissue that is capable to transform potential energy into kinetic energy. This process is due to the transformation of chemical energy into mechanical energy to enhance the movements and all the daily activities. However, muscular tissues can be affected by some pathologies associated with genetic alterations that affect the expression of proteins. As the muscle is a highly organized structure in which most of the signaling pathways and proteins are related to one another, pathologies may overlap. Duchenne muscular dystrophy (DMD) is one of the most severe muscle pathologies triggering degeneration and muscle necrosis. Several mathematical models have been developed to predict muscle response to different scenarios and pathologies. The aim of this review is to describe DMD and Becker muscular dystrophy in terms of cellular behavior and molecular disorders and to present an overview of the computational models implemented to understand muscle behavior with the aim of improving regenerative therapy., (© 2024 Wiley Periodicals LLC.)

Various protocols have been proven effective in the directed differentiation of mouse and human pluripotent stem cells into skeletal muscles and used to study myogenesis. Current 2D myogenic differentiation protocols can mimic muscle development and its alteration under pathological conditions such as muscular dystrophies. 3D skeletal muscle differentiation approaches can, in addition, model the interaction between the various cell types within the developing organoid. Our protocol ensures the differentiation of human embryonic/induced pluripotent stem cells (hESC/hiPSC) into skeletal muscle organoids (SMO) via cells with paraxial mesoderm and neuromesodermal progenitors' identity and further production of organized structures of the neural plate margin and the dermomyotome. Continuous culturing omits neural lineage differentiation and promotes fetal myogenesis, including the maturation of fibroadipogenic progenitors and PAX7-positive myogenic progenitors. The PAX7 progenitors resemble the late fetal stages of human development and, based on single-cell transcriptomic profiling, cluster close to adult satellite cells of primary muscles. To overcome the limited availability of muscle biopsies from patients with muscular dystrophy during disease progression, we propose to use the SMO system, which delivers a stable population of skeletal muscle progenitors from patient-specific iPSCs to investigate human myogenesis in healthy and diseased conditions. Key features • Development of skeletal muscle organoid differentiation from human pluripotent stem cells, which recapitulates myogenesis. • Analysis of early embryonic and fetal myogenesis. • Provision of skeletal muscle progenitors for in vitro and in vivo analysis for up to 14 weeks of organoid culture. • In vitro myogenesis from patient-specific iPSCs allows to overcome the bottleneck of muscle biopsies of patients with pathological conditions., Competing Interests: Competing interestsThe authors declare that there are no conflicts of interest regarding the publication of this paper., (©Copyright : © 2024 The Authors; This is an open access article under the CC BY license.)

Summary: Somatic stem cells expand massively during tissue regeneration, which might require control of cell fitness, allowing elimination of non-competitive, potentially harmful cells. How or if such cells are removed to restore organ function is not fully understood. Here, we show that a substantial fraction of muscle stem cells (MuSCs) undergo necroptosis because of epigenetic rewiring during chronic skeletal muscle regeneration, which is required for efficient regeneration of dystrophic muscles. Inhibition of necroptosis strongly enhances suppression of MuSC expansion in a non-cell-autonomous manner. Prevention of necroptosis in MuSCs of healthy muscles is mediated by the chromatin remodeler CHD4, which directly represses the necroptotic effector Ripk3, while CHD4-dependent Ripk3 repression is dramatically attenuated in dystrophic muscles. Loss of Ripk3 repression by inactivation of Chd4 causes massive necroptosis of MuSCs, abolishing regeneration. Our study demonstrates how programmed cell death in MuSCs is tightly controlled to achieve optimal tissue regeneration.

Background: Muscle MRI is of increasing importance for neuromuscular patients to detect changes in muscle volume, fat-infiltration, and edema. We developed a method for semi-automated segmentation of muscle MRI datasets.Methods: An active contour-evolution algorithm implemented within the ITK-SNAP software was used to segment T1-weighted MRI, and to quantify muscle volumes of neuromuscular patients (n = 65).Results: Semi-automated compared with manual segmentation was shown to be accurate and time-efficient. Muscle volumes and ratios of thigh/lower leg volume were lower in myopathy patients than in controls (P < .0001; P < .05). We found a decrease of lower leg muscle volume in neuropathy patients compared with controls (P < .01), which correlated with clinical parameters. In myopathy patients, muscle volume showed a positive correlation with muscle strength (rleft = 0.79, pleft  < .0001). Muscle volumes were independent of body mass index and age.Conclusions: Our method allows for exact and time-efficient quantification of muscle volumes with possible use as a biomarker in neuromuscular patients. [ABSTRACT FROM AUTHOR]

Protein O-glucosyltransferase 1 (POGLUT1) activity is critical for the Notch signaling pathway, being one of the main enzymes responsible for the glycosylation of the extracellular domain of Notch receptors. A biallelic mutation in the POGLUT1 gene has been reported in one family as the cause of an adult-onset limb-girdle muscular dystrophy (LGMD R21; OMIM# 617232). As the result of a collaborative international effort, we have identified the first cohort of 15 patients with LGMD R21, from nine unrelated families coming from different countries, providing a reliable phenotype–genotype and mechanistic insight. Patients carrying novel mutations in POGLUT1 all displayed a clinical picture of limb-girdle muscle weakness. However, the age at onset was broadened from adult to congenital and infantile onset. Moreover, we now report that the unique muscle imaging pattern of "inside-to-outside" fatty degeneration observed in the original cases is indeed a defining feature of POGLUT1 muscular dystrophy. Experiments on muscle biopsies from patients revealed a remarkable and consistent decrease in the level of the NOTCH1 intracellular domain, reduction of the pool of satellite cells (SC), and evidence of α-dystroglycan hypoglycosylation. In vitro biochemical and cell-based assays suggested a pathogenic role of the novel POGLUT1 mutations, leading to reduced enzymatic activity and/or protein stability. The association between the POGLUT1 variants and the muscular phenotype was established by in vivo experiments analyzing the indirect flight muscle development in transgenic Drosophila, showing that the human POGLUT1 mutations reduced its myogenic activity. In line with the well-known role of the Notch pathway in the homeostasis of SC and muscle regeneration, SC-derived myoblasts from patients' muscle samples showed decreased proliferation and facilitated differentiation. Together, these observations suggest that alterations in SC biology caused by reduced Notch1 signaling result in muscular dystrophy in LGMD R21 patients, likely with additional contribution from α-dystroglycan hypoglycosylation. This study settles the muscular clinical phenotype linked to POGLUT1 mutations and establishes the pathogenic mechanism underlying this muscle disorder. The description of a specific imaging pattern of fatty degeneration and muscle pathology with a decrease of α-dystroglycan glycosylation provides excellent tools which will help diagnose and follow up LGMD R21 patients. [ABSTRACT FROM AUTHOR]

Myopathies are a common manifestation of endocrine disorders. Endocrine myopathies are often overlooked while considering differential diagnoses in patients with musculoskeletal symptoms. The hindrance to mobility and the musculoskeletal discomfort owing to these myopathies are important causes of disability and depreciated quality of life in these patients. Endocrine myopathies occur due to the effects of endogenous or iatrogenic hormonal imbalance on skeletal muscle protein and glucose metabolism, disrupting the excitation-contraction coupling. Abnormalities of the pituitary, thyroid, parathyroid, adrenal, and gonadal hormones have all been associated with myopathies and musculoskeletal symptoms. Endocrine myopathies can either be the complication of a secondary endocrine disorder or a presenting symptom of a missed underlying disorder. Therefore, an underlying endocrine abnormality must always be excluded in all patients with musculoskeletal symptoms. This review presents a compilation of various endocrine myopathies, their etiopathogenesis, clinical presentation, diagnostic modalities, and treatment protocols. [ABSTRACT FROM AUTHOR]

Kyphoscoliotic Ehlers‐Danlos syndrome associated with FKBP14 (FKBP14‐kEDS) is an ultrarare autosomal recessive disorder reported in less than 30 individuals so far. In its original description, emphasis was put on the mild muscle involvement. Further reports confirm that FKBP14‐kEDS is distinguishable from primary muscle disorders by the lack of progressive muscle disease. We report a 15‐year‐old girl with FKBP14‐kEDS as a result of the recurrent c.362dupC variant, who also showed severe involvement of the lower limb muscles. She never attained autonomous walking and presented significant lower limb weakness. Lower limb magnetic resonance imaging showed a pattern of multiple muscle involvement. Further musculoskeletal assessment revealed significant bone mass density reduction of the spine, unilateral congenital hip dysplasia, and occipitoatlantoaxial instability. This patient points out the existence of a wider phenotypic spectrum of FKBP14‐kEDS to include early onset muscle disease. [ABSTRACT FROM AUTHOR]

Muscular dystrophies have always been marginalized culturally and socially, particularly in underdeveloped and developing countries. Pakistan is facing significant dearth of “appropriately” trained neurologists and neuromuscular pathologists. A careful and methodical link between clinical, pathological and molecular analysis must be established before making a diagnosis in such cases. Increased collaboration between local and international neurology societies may add value to collaborative neuromuscular research and education in Pakistan, both in community and health sectors. These goals are all achievable but require persistence, dedicated workforce, and positive efforts to meet them.

Chick embryonic cells can be used to develop an easy and economical in vitro model for conducting studies on the disease muscle dystrophy (MD). For this, the limb myoblasts from 11th day chick embryo were isolated and cultured. To this muscle cell culture, anti-dystroglycan antibody (IIH6) was added so as to target the α-dystroglycan and disrupt the connection between the cytoskeletal proteins and the extracellular matrix (which is a characteristic feature of MD). Cells were allowed to differentiate further and the morphometrics and mRNA expression were studied. The IIH6-treated muscle cells displayed changes in morphometry, contractibility, and also atrophy was observed when compared to the control cultures. Concomitant gene expression studies showed an upregulation in TGF-β expression, while the muscle sculpture genes MYOD1, MYF5, LAMA2 and MYOG were downregulated resembling the MD in vivo. This simple and cost-effective method can be useful in studies to further understand the disease mechanism and also in conducting initial studies on effect of novel pharmacological agents. [ABSTRACT FROM AUTHOR]

Abstract Duchenne muscular dystrophy (DMD) is characterized by a severe and progressive destruction of muscle fibers associated with altered Ca2+ homeostasis. We have previously shown that the IP 3 receptor (IP 3 R) plays a role in elevating basal cytoplasmic Ca2+ and that pharmacological blockade of IP 3 R restores muscle function. Moreover, we have shown that the IP 3 R pathway negatively regulates autophagy by controlling mitochondrial Ca2+ levels. Nevertheless, it remains unclear whether IP 3 R is involved in abnormal mitochondrial Ca2+ levels, mitochondrial dynamics, or autophagy and mitophagy observed in adult DMD skeletal muscle. Here, we show that the elevated basal autophagy and autophagic flux levels were normalized when IP 3 R was downregulated in mdx fibers. Pharmacological blockade of IP 3 R in mdx fibers restored both increased mitochondrial Ca2+ levels and mitochondrial membrane potential under resting conditions. Interestingly, mdx mitochondria changed from a fission to an elongated state after IP 3 R knockdown, and the elevated mitophagy levels in mdx fibers were normalized. To our knowledge, this is the first study associating IP 3 R1 activity with changes in autophagy, mitochondrial Ca2+ levels, mitochondrial membrane potential, mitochondrial dynamics, and mitophagy in adult mouse skeletal muscle. Moreover, these results suggest that increased IP 3 R activity in mdx fibers plays an important role in the pathophysiology of DMD. Overall, these results lead us to propose the use of specific IP 3 R blockers as a new pharmacological treatment for DMD, given their ability to restore both autophagy/mitophagy and mitochondrial function. Highlights • IP 3 R knockdown restored basal autophagy levels and autophagy flux in mdx muscle fibers. • IP 3 R blockade restored mitochondrial Ca2+ levels and mitochondrial membrane potential in mdx fibers. • IP 3 R knockdown restored mitochondria in mdx fibers to an elongated state. • IP 3 R knockdown restored mitochondrial dynamics in mdx fibers by decreasing fission protein levels. • IP 3 R knockdown normalized mitophagy in mdx fibers by modifying the levels of various proteins. [ABSTRACT FROM AUTHOR]

This study introduces local pattern texture anisotropy as a novel parameter to differentiate healthy and disordered muscle and to gauge the severity of muscle impairments based on B-mode ultrasound images. Preliminary human results are also presented. A local pattern texture anisotropy index (TAI) was computed in one region of interest in the short head of the biceps brachii. The effects of gain settings and box sizes required for TAI computation were investigated. Between-day reliability was studied in patients with sporadic inclusion body myositis (n = 26). The ability of the TAI to discriminate dystrophic from healthy muscle was evaluated in patients with Duchenne muscular dystrophy and healthy controls (n = 16). TAI values were compared with a gray-scale index (GSI). TAI values were less influenced by gain settings than were GSI values. TAI had lower between-day variability (typical error = 2.3%) compared with GSI (typical error = 2.3% vs. 8.3%, respectively). Patients with Duchenne muscular dystrophy had lower TAIs than controls (0.76 ± 0.06 vs. 0.87 ± 0.03, respectively, p <0.05). At 40% gain, TAI values correlated with percentage predicted elbow flexor strength in inclusion body myositis (R = 0.63, p <0.001). The TAI may be a promising addition to other texture-based approaches for quantitative muscle ultrasound imaging. [ABSTRACT FROM AUTHOR]

Mechanotransduction is a process where cells sense their surroundings and convert the physical forces in their environment into an appropriate response. Calcium plays a crucial role in the translation of such forces to biochemical signals that control various biological processes fundamental in muscle development. The mechanical stimulation of muscle cells may for example result from stretch, electric and magnetic stimulation, shear stress, and altered gravity exposure. The response, mainly involving changes in intracellular calcium concentration then leads to a cascade of events by the activation of downstream signaling pathways. The key calcium-dependent pathways described here include the nuclear factor of activated T cells (NFAT) and mitogen-activated protein kinase (MAPK) activation. The subsequent effects in cellular homeostasis consist of cytoskeletal remodeling, cell cycle progression, growth, differentiation, and apoptosis, all necessary for healthy muscle development, repair, and regeneration. A deregulation from the normal process due to disuse, trauma, or disease can result in a clinical condition such as muscle atrophy, which entails a significant loss of muscle mass. In order to develop therapies against such diseased states, we need to better understand the relevance of calcium signaling and the downstream responses to mechanical forces in skeletal muscle. The purpose of this review is to discuss in detail how diverse mechanical stimuli cause changes in calcium homeostasis by affecting membrane channels and the intracellular stores, which in turn regulate multiple pathways that impart these effects and control the fate of muscle tissue.

The maintenance of muscle mass and its ability to function relies on a bioenergetic efficient mitochondrial network. This network is highly impacted by fusion and fission events. We have recently shown that the acute deletion of the fusion protein Opa1 induces muscle atrophy, systemic inflammatory response, precocious epithelial senescence, and premature death that are caused by muscle-dependent secretion of FGF21. However, both fusion and fission machinery are suppressed in aging sarcopenia, cancer cachexia, and chemotherapy-induced muscle wasting. We generated inducible muscle-specific Opa1 and Drp1 double-knockout mice to address the physiological relevance of the concomitant impairment of fusion and fission machinery in skeletal muscle. Here we show that acute ablation of Opa1 and Drp1 in adult muscle causes the accumulation of abnormal and dysfunctional mitochondria, as well as the inhibition of autophagy and mitophagy pathways. This ultimately results in ER stress, muscle loss, and the reduction of force generation. However, the simultaneous inhibition of the fission protein Drp1 when Opa1 is absent alleviates FGF21 induction, oxidative stress, denervation, and inflammation rescuing the lethal phenotype of Opa1 knockout mice, despite the presence of any muscle weakness. Thus, the simultaneous inhibition of fusion and fission processes mitigates the detrimental effects of unbalanced mitochondrial fusion and prevents the secretion of pro-senescence factors.

Objective There is increasing evidence that an involvement of central nervous system (CNS) can occur in several myopathies. Transcranial magnetic stimulation (TMS) may represent a valuable tool for investigating important neurophysiological and pathophysiological aspects of cortical involvement in neuromuscular disorders. In this review paper we aimed to perform a systematic search of the studies employing TMS techniques in subjects suffering from myopathies. Methods A literature search was conducted using PubMed and Embase. We identified and reviewed 9 articles matching the inclusion criteria. One hundred twenty patients were included in these studies, which have applied TMS in patients with muscle disorders. Results To date, a few studies using TMS have been performed in myopathic patients and detected subclinical abnormalities in cortical reactivity and plasticity. The most consistent finding was a decrease in intracortical inhibition, which likely represents a non-specific compensatory mechanism of the CNS in an attempt to overcome the muscle deficit through an increase of the motor cortex output to deficient muscles. Conclusions Application of TMS to characterize the pathophysiology of the CNS in these subjects appears to be safe and may lead to the development of valuable biomarkers. Well-defined motor cortical excitability patterns can be identified in the different muscle diseases, even if preliminary findings should be confirmed in future studies in larger cohorts of patients. Significance TMS studies may shed new light on the physiological and pathophysiological mechanisms underlying the cortical involvement in muscle disorders. [ABSTRACT FROM AUTHOR]

Many muscular dystrophies, including lethal Duchenne muscular dystrophy, are incurable and require the sustained application of drugs that have only minor treatment effects and serious negative side effects. The mechanism of siRNA-mediated transcriptional gene regulation (TGR) appears to have a long-lasting effect and may be a viable solution to treat muscle disorders because single or at least rarely repeated therapies would be used. For the best results, siRNA should be delivered to all disease affected muscles, and systemic delivery of siRNA through blood vessels is probably the only applicable choice to achieve this goal. Unfortunately, there are many challenges to overcome such as siRNA degradation in blood, renal clearance, blood–muscle barrier, cell entry and endosomal escape. By exploiting and considering the unique features of muscles and the mechanism of TGR, we will discuss the possible ways to induce TGR in muscles by using non-viral systemic siRNA delivery methods. [ABSTRACT FROM AUTHOR]

Muscular dystrophies are a group of genetic neuromuscular disorders characterized by skeletal muscle weakness and wasting. Our aim was to observe the facial morphology and certain features of oro-facial function in patients with different forms of muscle dystrophy. This study was conducted in the Division of Morbid Anatomy and Histopathology at University of Health Sciences after ethical review committee approval. A total of 100 patients with clinical suspicion of muscular dystrophy reporting at the Children Hospital and Institute of Child Health and Pakistan Society of Rehabilitation of Disabled (PSRD) Lahore from January 2010-2015were included.Among 100 patients, 77 were males while 23 were females. Mean age for onset of muscle weakness was 6.40± 4.226 years. A total of 6 patients presented with dysmorphic faces and jaw muscle weakness along with other characteristics suggesting other forms of muscular dystrophies. Muscular dystrophies involve facial morphology and alter the functioning of jaw muscles that carries both diagnostic and therapeutic implications. [ABSTRACT FROM AUTHOR]

Dysferlinopathy, caused by a dysferlin gene mutation, is a clinically heterogeneous autosomal recessive muscle disease characterized by progressive muscle degeneration. The dysferlin protein's functions and dysferlinopathy disease pathogenesis are not fully explored, and there is no specific treatment available that can alter the disease progression. This study uses publicly available dysferlinopathy patient microarray data to construct a gene co-expression network and investigates significant cellular pathways and their key players in dysferlinopathy pathogenesis. Extracellular matrix deposition, inflammation, mitochondrial abnormalities and protein degradation were found to be important in dysferlinopathy. Out of the hub genes, OXR1 and TIMP1 were selected through literature search as candidate genes for possible biomarker and molecular therapeutic target studies. A recently identified muscular dystrophy gene TOR1AIP1 was detected as a hub gene in dysferlinopathy. Co-expression and protein sequence feature analysis were adopted to predict TOR1AIP1 's function. Our results suggest that LAP1 protein encoded by TOR1AIP1 may play a role in protein degradation possibly through transcriptional regulation in muscle tissue. These findings extend dysferlinopathy pathogenesis by presenting key genes and also suggest a novel function for a poorly characterized gene. [ABSTRACT FROM AUTHOR]

MRI's T 2 relaxation time is a valuable biomarker for neuromuscular disorders and muscle dystrophies. One of the hallmarks of these pathologies is the infiltration of adipose tissue and a loss of muscle volume. This leads to a mixture of two signal components, from fat and from water, to appear in each imaged voxel, each having a specific T 2 relaxation time. In this proof-of-concept work, we present a technique that can separate the signals from water and from fat within each voxel, measure their separate T 2 values, and calculate their relative fractions. The echo modulation curve (EMC) algorithm is a dictionary-based technique that offers accurate and reproducible mapping of T 2 relaxation times. We present an extension of the EMC algorithm for estimating subvoxel fat and water fractions, alongside the T 2 and proton-density values of each component. To facilitate data processing, calf and thigh anatomy were automatically segmented using a fully convolutional neural network and FSLeyes software. The preprocessing included creating two signal dictionaries, for water and for fat, using Bloch simulations of the prospective protocol. Postprocessing included voxelwise fitting for two components, by matching the experimental decay curve to a linear combination of the two simulated dictionaries. Subvoxel fat and water fractions and relaxation times were generated and used to calculate a new quantitative biomarker, termed viable muscle index, and reflecting disease severity. This biomarker indicates the fraction of remaining muscle out of the entire muscle region. The results were compared with those using the conventional Dixon technique, showing high agreement (R = 0.98, p < 0.001). It was concluded that the new extension of the EMC algorithm can be used to quantify abnormal fat infiltration as well as identify early inflammatory processes corresponding to elevation in the T 2 value of the water (muscle) component. This new ability may improve the diagnostic accuracy of neuromuscular diseases, help stratification of patients according to disease severity, and offer an efficient tool for tracking disease progression., (© 2023 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Identifying the mutated gene that produces a particular muscle dystrophy is difficult because different genotypes may share a phenotype and vice versa. Muscle MRI is a useful tool to recognize patterns of muscle involvement in patients with muscle dystrophies and to guide the diagnosis process. The radiologic pattern of muscle involvement in patients with mutations in the EMD and LMNA genes has not been completely established. Our objective is to describe the pattern of muscle fatty infiltration in patients with mutations in the EMD and in the LMNA genes and to search for differences between the two genotypes that could be helpful to guide the genetic tests. We conducted a national multicenter study in 42 patients, 10 with mutations in the EMD gene and 32 with mutations in the LMNA gene. MRI or CT was used to study the muscles from trunk to legs. Patients had a similar pattern of fatty infiltration regardless of whether they had the mutation in the EMD or LMNA gene. The main muscles involved were the paravertebral, glutei , quadriceps , biceps , semitendinosus , semimembranosus , adductor major , soleus , and gastrocnemius . Involvement of peroneus muscle, which was more frequently affected in patients with mutations in the EMD gene, was useful to differentiate between the two genotypes. Muscle MRI/CT identifies a similar pattern of muscle fatty infiltration in patients with mutations in the EMD or the LMNA genes. The involvement of peroneus muscles could be useful to conduct genetic analysis in patients with an EDMD phenotype. [ABSTRACT FROM AUTHOR]