Desminopathy is a myofibrillar myopathy caused by pathogenic variants in DES and characterized by heterogeneous clinical and imaging manifestations. Although preferential muscle involvement has been described, systematic whole-body computed tomography (CT) analyses remain limited. This study aimed to characterize patterns of skeletal muscle involvement and imaging-defined severity in desminopathy using whole-body CT. Whole-body CT scans from 14 adults with DES-related myopathy were evaluated using a modified Mercuri score across 43 muscles. Multivariate analyses were applied to characterize patterns of muscle involvement, define imaging-based severity groups, and assess variable associations. Fourteen adult patients (11 males, 3 females; age range 29-69 years) with symptom duration ranging from 2 to 29 years were included. Early involvement was observed across thigh musculature, with semitendinosus consistently affected. Extensor digitorum longus, fibularis brevis, and tibialis posterior demonstrated discriminatory utility across severity groups. Increasing severity was associated with broader involvement of thigh, gluteal, trunk, and lower-leg muscles. Variant location showed domain-associated tendencies, with Coil 2B variants associated with prominent vastus involvement and trunk-directed patterns, whereas tail-domain variants were associated with greater posterior thigh and trunk involvement. Side-to-side asymmetry occurred variably and was most consistently observed in tibialis anterior. Whole-body CT imaging delineates coordinated, severity-dependent patterns of muscle involvement in desminopathy. Our work illustrates the value of whole-body CT for characterizing global patterns of muscle involvement and for informing future imaging-based studies in desminopathy, including larger cohorts and longitudinal investigations to better define disease progression and imaging biomarkers.

Recent studies have focused on oral frailty and hypofunction, and their relationship with swallowing function and dysphagia. These play especially important roles in patients with dysphagia in medical-dental cooperation at acute hospitals. This study aimed to assess oral frailty, in terms of nutritional intake by evaluating oral and swallowing functions simultaneously, in patients consulting at an acute hospital. This cross-sectional study was conducted at the Center for Dysphagia of Tohoku University Hospital and involved a comprehensive survey of 183 patients. Their oral function and oral status were evaluated, which included factors such as poor oral hygiene, oral dryness, tongue-lip motor function, tongue pressure, and masticatory performance. Additionally, swallowing status was evaluated using various methods, including a questionnaire related to swallowing, Hyodo-Komagane score, modified water-swallowing, and repetitive saliva swallowing tests. This thorough approach ensured the validity and reliability of our findings. Approximately 60% of patients had head and neck tumours, degenerative diseases, and muscular diseases. Therefore, a high prevalence of oral hypofunction was observed. Furthermore, since 41.5% of patients had limited tongue movement, a characteristic correlation existed between the oral diadochokinesis and Hyodo-Komagane score. These results suggest that oral dryness score, oral diadochokinesis, and tongue pressure are associated with oral hypofunction and dysphagia. Additionally, patients with hypofunction and decreased tongue pressure may have hypopharyngeal residuals. The medical-dental cooperation in an acute hospital allows for the simultaneous assessment of oral and swallowing functions. This suggests a potential to contribute to the practice of safe oral intake and appropriate rehabilitation.

Sarcopenia is a muscle disease characterized by the progressive loss of muscle mass, strength, and function. Despite evolving definitions, validated diagnostic tools for younger individuals, especially those with cancer or chronic diseases, remain lacking. Oncological treatments can lead to severe muscle deconditioning. Many patients face limited follow-up and remain physically diminished in post-cancer period. We aimed to determine the prevalence of sarcopenia in post-cancer patients and to highlight its occurrence even in younger individuals and long after completion of oncological treatments. We performed prospective and standardized muscle assessment through: physical activity questionnaires (International Physical Activity Questionnaire [IPAQ] and Strength, Assistance with walking, Rise from a chair, Climb stairs and Falls [SARC-F]); functional tests (grip strength, 6-minute walk, and 30-second chair stand tests); and appendicular lean mass (ALM) index measurement by dual-energy X-ray absorptiometry (DXA; ALM/height² in kg/m²). Ninety-eight patients (68 females) were included (age (mean±SD) 53.8±11.0 years and body mass index (BMI) 27.8±6.4 kg/m²). Fifty-five had solid tumors (41 metastatic) with a post-treatment duration of 20.3±21.75 months. SARC-F score was 1.5±1.6. Grip strength and ALM index were 27.3±11.7 kg and 6.4±1.4 kg/m² respectively. Considering cancer as a sarcopenia at risk status, we used European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria and identified 27 (27.6%) patients with sarcopenia. Patients with sarcopenia were younger (50.2±11.6 vs 55.2±12.0 years; p=0.07), more frequently in remission and long after treatment, and had lower BMI (23.3±3.2 vs 29.5±6.5 kg/m²; p<0.0001) compared to patients without sarcopenia. When using SARC-F for screening, only 5 patients were detected, underlining its poor sensitivity in this setting. Sarcopenia is highly prevalent in post-cancer patients including younger individuals and those in long-term remission. The 2019 EWGSOP2 criteria, combining ALM and functional tests, effectively identified sarcopenia but screening with SARC-F may not be suitable in the post-cancer population.

Autophagy has been extensively studied in a variety of pathologies, including neurological disorders, cancers, muscle diseases, aging, and cardiovascular diseases. Doxorubicin (Dox) is a potent anticancer drug widely used to treat various cancers. Despite its therapeutic benefits, it has cardiotoxic side effects, interfering with its clinical application. Dox-induced cardiomyopathy (DIC) is one of the most prominent and lethal side effects associated with the use of Dox. Numerous investigations have revealed that Dox administration impacts autophagy; however, the precise mechanism by which Dox modifies this process remains unclear, as the role of autophagy in heart tissue is controversial, ranging from being cytoprotective to cytotoxic. Various therapeutic interventions, including pharmacological drugs and natural products, have been reported to influence the autophagic flux in DIC. In this review, we explore the therapeutic potential of autophagy modulation in DIC, focusing on how various pharmacological drugs and natural products influence autophagy to mitigate cardiac damage. This review uniquely emphasizes the mechanistic role of autophagy in DIC and provides a comprehensive analysis of therapeutic interventions targeting autophagy as a strategy for cardioprotection.

Beyond arrhythmias: Exploring heart failure in arrhythmogenic cardiomyopathy.

Movement disorders associated with neuromuscular diseases are often underrecognized, yet they represent a distinct clinical entity. Abnormalities in areas of the peripheral nervous system, i.e., nerves and muscles, can stem from dysfunction of ion channels and proteins involved in membrane excitability. Hyperexcitability of peripheral motor nerves presents as cramps, stiffness, abnormal posture and gait, as well as changes in motor unit potentials during electromyography studies; hence, it may be classified as a movement problem. Etiologies range from hereditary, immune-mediated, or may be secondary to structural changes. This review focuses on peripheral nervous system and muscle-derived movement disorders associated with autoantibodies. It aims to highlight immune-mediated peripheral nerve hyperexcitability syndromes, stiff-person spectrum disorders, and immune-mediated rippling muscle disease (a movement disorder of muscular origin). It also discusses pathophysiology, diagnosis (particularly immunologic markers), and therapeutics.

ABSTRACT Macroautophagy/autophagy is a key regulator of muscle mass and of muscle adaptation to stress and defective autophagy is a feature of many muscle disorders. Still, how changes in autophagic flux influence the integrity and function of differentiated muscle fibers remains under-documented. Specifically, links between autophagy and mechanisms involved in Ca2+ homeostasis and excitation-contraction coupling are largely unexplored. We developed an assay to monitor autophagy modulation in mouse muscle fibers maintained in culture. Exposure to 3-methyladenine, an inhibitor of autophagy initiation, reduced the density of autophagic vesicles. Conversely, hydroxychloroquine, a blocker of autolysosome formation, as well as two MTOR inhibitors that activate autophagy, rapamycin and torin-1, enhanced the vesicle density. The density of lysosomal vesicles was increased by MTOR inhibitors and by hydroxychloroquine, but insensitive to 3-methyladenine. Measurements of Ca2+ signals associated with contractile activation revealed that voltage-activated sarcoplasmic reticulum Ca2+ release was unaffected by torin-1 but was depressed in 3-methyladenine- and in hydroxychloroquine-exposed fibers, suggesting that restraining autophagic flux is detrimental to excitation contraction coupling. The density of the inner plasma membrane network that carries the electrical excitation was depressed by 3-methyladenine and hydroxychloroquine, likely contributing to the function defect. Results establish that autophagic flux is preserved and can be manipulated in cultured muscle fibers, and revealed the power of the approach to tackle the cellular and subcellular consequences of autophagy modulation. They also uncover the possibility that autophagy is a determinant of maintenance and/or function of excitation-contraction coupling, with a potential role in several muscle disease situations. Abbreviations: 3-MA: 3-methyladenine; EC: excitation-contraction; HCQ: hydroxychloroquine; MTM1: myotubularin 1; RYR1: ryanodine receptor 1.

BackgroundDistal myopathies (DMs) comprise a heterogeneous group of hereditary muscle diseases characterized by predominant distal muscle weakness and atrophy overlapping with hereditary neuropathies, leading to diagnostic delays or misclassification.ResultsWe conducted a retrospective analysis of 125 patients from 103 families with DMs revealed at a federal genetics referral center in Russia from 2010 to 2025, representing the largest Russian DM cohort. Causative variants were identified in 20 genes, most commonly in the GNE (30.1%), DYSF (13.6%), and TTN (9.7%) genes. Although distal muscle involvement predominated, lower limb muscle magnetic resonance imaging (MRI) showed proximal involvement in 93.4% (71/76) of cases regardless of disease stage. Across the cohort, gracilis, rectus femoris, and tibialis posterior were relatively spared. Referral misdiagnosis as hereditary neuropathy occurred in 32.8% (41/125) of cases. To characterize diagnostic pitfalls, we compared patients initially referred with neuropathy to those referred with DM. We demonstrated that group differences were evident solely in the needle electromyography (EMG) reports, while clinical features and lower limb muscle MRI data were broadly comparable. We analyzed the probable causes of EMG misinterpretations, which most commonly included severe spontaneous activity being mistaken for active denervation, high-amplitude motor unit potentials being misclassified as neurogenic, and, in some cases, the wrong choice of muscle for the study.ConclusionAccording to our data, one-third of patients with DM were initially referred for suspected neuropathy. In many cases, misclassification was likely due to pitfalls in EMG interpretation, highlighting the need for careful EMG analysis in patients with myopathies.

Fibrosing myopathy in systemic sclerosis: Treatment response and clinical outcomes in a distinct subset.

Muscle passive and active function is dependent on the extracellular matrix (ECM). In diseases characterized by muscle fibrosis, namely Duchenne Muscular Dystrophy (DMD), the ECM contributes to deficits in muscle mechanical function and regeneration. Because fibrosis is often viewed as irreversible in DMD and other muscle diseases, there is great incentive to develop anti-fibrotic therapies to prevent or reverse fibrosis. In this study we tested the effectiveness of intramuscular injections of non-specific Clostridium histolyticum collagenase (CCH) on reducing ECM contents and rescuing muscle mechanical function in D2.mdx mice, models of DMD. We performed unilateral injections of collagenase into the tibialis anterior and gastrocnemius in WT and D2.mdx mice. We measured in vivo plantarflexion strength, ex vivo muscle mechanical function, immunohistochemistry, and total and cross-linked collagen content. We found that crude CCH was effective at digesting the muscle ECM but did not provide a therapeutic benefit evidenced by induction of muscle weakness and bleeding within 24h after CCH injections, and a thickened basal lamina after 7 days. We conclude that future studies testing collagenase as an anti-fibrotic should use a collagenase specific to fibrillar collagens and a paired physical therapy protocol to better preserve muscle function while reducing fibrosis.

Muscle fibrosis is a major driver of progression in diverse myopathies, yet the conserved molecular mediators of this process in humans remain poorly defined. Here, we identify collagen VI as a common regeneration-impairing extracellular matrix (ECM) component across three distinct human myopathies: Duchenne Muscular Dystrophy (DMD), Oculopharyngeal Muscular Dystrophy (OPMD), and Inclusion Body Myositis (IBM). Proteomic profiling of fibrotic biopsies reveals consistent upregulation of collagen VI and laminin γ1, alongside disease-specific alterations. Fibroadipogenic progenitors (FAPs) are the predominant source of these ECM components, including collagen VI and laminin γ1. Functionally, xenotransplantation of patient-derived FAPs into regenerating mouse muscle induces localized collagen deposition, myofiber atrophy, and depletion of Pax7⁺ muscle stem cells. Mechanistic assays demonstrate that FAP-derived collagen VI is sufficient to impair myogenic fusion, while silencing COL6 in patient FAPs restores fusion capacity, directly linking pathological collagen VI deposition to regeneration failure. Our findings uncover collagen VI as a conserved effector of fibrosis and stem cell niche disruption in human myopathies, positioning it as a potential therapeutic target across genetically and clinically distinct muscle diseases.

Striated muscles exhibit remarkable structural and functional specialization that enables precise control of force production, contractile kinetics, and energetic efficiency. Although vertebrate skeletal and cardiac muscles have been extensively studied, comparative analyses across animal phyla reveal that many molecular and biophysical principles governing muscle performance are deeply conserved. Insects, in particular, possess highly differentiated muscle types that provide powerful systems for dissecting the regulation of contraction, elasticity, and force generation at the level of the sarcomere. In this review, we integrate insights from insect and vertebrate muscles to highlight conserved and divergent features of sarcomere organization and myofilament composition. We focus on major contractile and regulatory proteins, including actin, myosin, troponin, tropomyosin, and elastic proteins, emphasizing how isoform diversity fine-tunes muscle function. We discuss the biomedical relevance of invertebrate models for understanding muscle disease mechanisms, including congenital myopathies, sarcomeric protein-associated disorders, and muscular dystrophies. Finally, we examine how principles uncovered in insect muscles inform vertebrate cardiac physiology and skeletal muscle aging, positioning insect systems as complementary discovery platforms for advancing muscle biology.

Gastrointestinal (GI) involvement in myositis is a severe extra muscular manifestation with potentially life-threatening outcomes. However, it remains poorly characterized. We aimed to evaluate the prevalence of GI involvement in dermatomyositis (DM) and to describe its characteristics in anti-NXP2 DM. The prevalence of GI involvement across DM subgroups was assessed in a retrospective monocentric DM cohort (n = 119). It was further investigated in a retrospective multicentric cohort of anti-NXP2 DM (n = 48). GI involvement (defined as any symptomatic GI lesion, excluding isolated dysphagia) was considered severe when requiring surgery and/or intensive care unit admission. In the monocentric DM cohort, severe GI involvement was observed in 18% of anti-NXP2 patients and 6% of anti-MDA5 patients. Severe GI involvement was significantly more frequent in anti-NXP2 patients compared with other DM subgroups (hazard ratio 8.85 [95% CI 1.62-48.35]). In the multicentric anti-NXP2 cohort, severe GI involvement (including four digestive perforations and three digestive haemorrhages) occurred in 12.5% of patients. Anti-NXP2 patients with severe GI involvement were significantly younger (median age 24.5 vs 42.5 years; p< 0.01) and more frequently presented with facial oedema at diagnosis (83% vs 33%; p= 0.03). At the time of GI involvement, 78% of anti-NXP2 patients had concomitant skin and/or muscle disease activity. No deaths were reported. Severe GI involvement represents a life-threatening complication in DM and is mainly associated with anti-NXP2 antibody. In anti-NXP2 DM, young age and facial oedema are associated with severe GI involvement.

Skeletal muscle consists of a bundle of thousands of post-mitotic multinucleated cells (i.e., myofibers), in which myonuclei are evenly spaced and positioned at the periphery. This myonuclear positioning shapes myonuclear domain (MND) in myofibers, is essential for the transcriptional integrity of myofibers, is driven by the cytoskeleton and associated proteins and is required for proper myofiber functions. In numerous muscle diseases (i.e., myopathies), alteration of myonuclei localization contributes to myofiber dysfunction, supporting the need to better understand the fundamental mechanisms that regulate myonuclei dynamics in differentiated myofibers. In this study, we show that in Duchenne muscular dystrophy (DMD) myofibers, myonuclei are more dynamic and contribute to the failure in MND settings, suggesting enhanced myonuclear motility impacts myonuclear distribution. To identify new actors in MND settings, we performed a mass spectrometry (MS)-based proteomic analysis to identify microtubule-associated proteins (MAPs) in myotubes/myofibers and performed a siRNA screening on candidates. This approach highlighted NuMA1 as a new factor controlling myoblast fusion and myonuclear positioning through the control of nuclear-microtubule-organizing-center (n-MTOC) integrity and microtubule network orientation. Strikingly, while NuMA1 is restrained to myonuclei in mononucleated myoblasts, it progressively accumulates in the cytoplasm during muscle cell differentiation, preferentially with microtubule (MT) nucleation spots at the vicinity of the nuclear membrane. We identified that AMP Kinase activity has an essential role in NuMA1 nuclear/cytoplasmic accumulation through the specific phosphorylation on serine-1853 and the ability of myonuclei to accumulate NuMA1 is correlated to their motility in myofibers. Finally, we show that nuclear NuMA1 content is increased in DMD patients and mdx mouse model, contributing to more dynamic myonuclei that can be manipulated pharmacologically through the control of AMPK activity. Altogether, our data identifies a novel mechanism by which nuclear sequestration of a MAP allows to couple nuclear positioning and motion to MT organization along skeletal muscle differentiation.

3D cell culture, using a variety of bioengineering techniques, enables muscle cells to be cultured in more structural and functional biomimetic conditions than 2D cell culture. Here, we tested the ability of an engineered 3D skeletal muscle model to recapitulate in vivo metabolic muscle response. First, C2C12 myoblasts in 3D cultures showed improved myogenesis, attested by increased differentiation time, myotube formation, and gene expression of differentiated muscle markers. At the functional level, the 3D muscle culture displayed contractile properties and proper mitochondrial respiration. Second, to highlight the interest of such system we used primary myoblasts derived from myostatin knockout (Mstn−/−) mice. When compared to control wild‐types 3D myotubes, 3D myotubes made from Mstn−/− myoblasts exhibit a hypertrophic phenotype associated with a decrease mitochondrial oxygen consumption, consistent with the skeletal muscle characteristics of Mstn−/− mice. Our findings show that 3D primary myotubes retain their in vivo phenotype in culture. This provides a useful framework for studying the underlying mechanisms of a various genetic muscle diseases, as well as for screening therapeutic drugs.

In silico virtual knockout identifies PXDNL as a fibroblast-specific driver of sarcopenia and GABA as a potential modulator.

Integrated RNA sequencing and in vivo biosensor imaging define the early pathogenic cascade of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a lethal pediatric striated muscle disease caused by loss of dystrophin for which there is no cure. Cardiomyopathy is the leading cause of death amongst individuals with DMD, and effective therapeutics to treat DMD cardiomyopathy are a major unmet clinical need. This work investigated adeno-associated viral (AAV) gene therapy approaches to treat DMD cardiomyopathy by overexpression of the calcium binding proteins S100A1 and apoptosis repressor with caspase recruitment domains (ARC). Using the severe D2.mdx mouse model of DMD, we identified that S100A1 gene therapy improves the diastolic dysfunction associated with DMD cardiomyopathy, whereas ARC gene therapy prolongs survival. The combination of both S100A1 and ARC in a single bicistronic vector improves the long-term cardiac outcome and histopathology of D2.mdx mice, development of heart failure caused by micro-dystrophin expression, and exhibits safety via intracoronary delivery in a canine model of DMD. In addition to robust cardiac benefits, S100A1-ARC gene therapy benefits D2.mdx skeletal muscle function and histopathology when driven by a striated muscle promoter. Together, these findings indicate that S100A1-ARC gene therapy represents an effective treatment for DMD cardiomyopathy and may have therapeutic benefits in treating other forms of cardiomyopathy and muscle pathologies.

Quantitative ultrasound radiofrequency analysis for monitoring Parkinson's disease.

Desminopathies are a heterogeneous group of myofibrillar myopathies defined by the presence of desmin-positive aggregates that compromise cytoskeletal integrity in skeletal and cardiac muscle. Although desmin knockout models and several truncating mutations typically result in a functional null phenotype without inclusion body formation, the molecular consequences of specific stop-gain variants remain poorly understood. In this study, we investigated the pathogenic mechanism of a novel Desmin (DES) nonsense mutation, NM_001927.4:c.448 C > T; p.(Arg150Stop), previously identified in an Indian patient with congenital myopathy. This premature stop codon lies within the Linker 1 A domain and is predicted to generate a truncated protein lacking the C-terminal tail. To delineate its functional consequences, we used two complementary experimental approaches: transient overexpression of the Arg150Stop mutant in skeletal and cardiac myocytes, and a CRISPR/Cas9-engineered homozygous Arg150stop cardiomyocyte line (Destr-CRISPR). Both models consistently revealed the formation of persistent aggregate-like structures, in striking contrast to desmin knockout systems that do not generate inclusions. These aggregate-like structures disrupted actin filament organization, impaired filament bundling, and induced organelle mislocalization. Biochemical analysis indicated that the aggregates were resistant to proteasomal degradation, yet they were partially cleared by autophagy, underscoring a role for protein quality control pathways in modulating disease severity. Importantly, the Destr-CRISPR line demonstrated aggregate-driven pathology at endogenous levels, confirming that this mutation acts through a toxic gain-of-function mechanism rather than simple loss of desmin function. Our findings establish the Arg150Stop variant as a mechanistically distinct truncating mutation that generates aggregation-prone protein rather than a null state. By reproducing hallmark features of desminopathy in a physiologically relevant human cell models, this work not only broadens the known pathogenic spectrum of DES variants but also highlights aggregate formation as a central driver of cellular dysfunction and a promising therapeutic target in desminopathies.