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.

Dermatomyositis (DM) is often associated with malignancies but less commonly with plasma cell dyscrasias. Myoglobin nephropathy is an uncommon complication of inflammatory myopathies. This case describes a patient who presented with proteinuria because of myoglobin nephropathy caused by dermatomyositis. The dermatomyositis was paraneoplastic with an underlying smouldering multiple myeloma (SMM) diagnosed on investigation. Case report. A 58-year-old mixed-race gentleman was referred for sub-nephrotic proteinuria. Further history taking revealed a 1-month history of proximal muscle weakness and a 5-month history of skin changes suggestive of dermatomyositis. Additional testing showed no associated albuminuria. There was haematuria on the urine microscopy which, with the accompanying raised creatine kinase levels, suggested myoglobinuria. Kidney biopsy confirmed myoglobin nephropathy. Further testing was done to exclude paraneoplastic DM. Investigations for solid organ malignancies were negative. Plasma cell dyscrasia screening revealed an IgA kappa monoclonal band, which was confirmed with serum free light chain testing. A bone marrow biopsy confirmed the diagnosis of SMM based on the revised working group diagnostic criteria for multiple myeloma. This case serves as a reminder of the importance of clinical history and examination. Investigation in this case revealed an extrarenal cause of the proteinuria, and recognition of the presentation of DM led to further investigation for secondary causes. Routine screening for plasma cell dyscrasias is recommended as part of DM work-up to allow the diagnosis to be made early, prior to organ damage.

Equine lameness diagnosis is dominated by a joint- and tendon-centric paradigm. The standard diagnostic algorithm relies on gait observation, perineural and intrasynovial anesthesia, and cross-sectional imaging. It is directed almost exclusively at skeletal and articular structures. Myofascial trigger points (MTrPs) are hypersensitive, hyperirritable loci within taut bands of skeletal muscle. They produce local and referred pain on compression or contraction. In horses, MTrPs are a clinically relevant but systematically overlooked source of primary lameness. This review synthesises evidence from equine and comparative research. We argue that MTrPs can act as the primary-not merely secondary-cause of gait asymmetry, performance deficits, and pain behavior in horses. Key mechanisms include the energy crisis model of MTrP formation, peripheral and central sensitization, referred pain projection mimicking distal limb pathology, and the biomechanical consequences of MTrP-induced muscle inhibition on gait. Electrophysiological studies confirm that equine MTrPs show the same spontaneous electrical activity as human and animal MTrPs. Prevalence studies indicate that MTrPs are present in many sport horses. Dressage horses show particularly high prevalence in the cervical and thoracolumbar musculature. Of clinical importance is the referred pain phenomenon: MTrPs in proximal muscles such as the gluteus medius, longissimus lumborum, and biceps femoris may produce apparent distal limb pain. Such pain can be clinically indistinguishable from joint or tendon pathology. This has direct and underappreciated implications for diagnostic accuracy. We propose that systematic myofascial palpation should be integrated into the routine equine lameness workup as a first-tier diagnostic step. Rapid resolution of gait asymmetry following targeted MTrP treatment should be interpreted as supportive evidence of myofascial origin. We further delineate the clinically relevant trigger point activity spectrum from active to latent states, address differential diagnoses such as Lyme-associated diffuse myalgia and primary myopathies (PSSM2, MIM, IMM), summarise the principal therapeutic modalities used in equine MTrP management, and examine biotensegrity as a mechanobiological framework explaining the multisegmental fascial effects of myofascial dysfunction.

Background Atrial fibrillation (AF) is a leading cause of stroke, cardiovascular morbidity, and mortality. Atrial myopathy, characterized by progressive metabolic, electrical, and structural changes, creates the arrhythmogenic substrate that drives AF. Defining the key drivers of atrial myopathic processes is essential for targeted therapies that can mitigate AF progression. Here we explore how reduced ERBB4 expression contributes to the development of left atrial myopathy. Methods We analyzed the Cleveland Clinic Biobank to compare left atrial ERBB4 levels in patients grouped by AF diagnosis. To investigate the impact of reduced ERBB4 levels on atrial tissue substrate, we created mouse models of cardiac-specific Erbb4 deficiency using Mlc2a (myosin light chain 2a)-Cre. Comprehensive physiological assessments were performed. Transcriptomic analyses of the left atrium were performed in an Erbb4 haploinsufficient mouse model and compared with human atrial datasets. Molecular validation of key dysregulated pathways was performed. Results We found that left atrial ERBB4 levels are reduced in patients with AF. Adult cardiomyocyte-specific Erbb4 heterozygous (Erbb4fl/+;Mlc2a-Cre) mice exhibited prolonged P-wave duration in the absence of ventricular dysfunction. Left atrial transcriptomic analysis in Erbb4 haploinsufficient mice showed upregulation of pathways related to fibrosis, apoptosis, and coagulation, and downregulation of pathways related to fatty acid metabolism and mitochondrial function, mirroring changes observed in pressure overload mouse models. A cross-species transcriptomic comparison revealed significant overlap between ERBB4-correlated gene expression and functional pathways in adult human atria and mice with Erbb4 haploinsufficiency. Validating the transcriptomic data, protein and functional assays demonstrated increased fibrosis, apoptosis, and oxidative stress in the mutant left atrial tissue. Conclusion Left atrial ERBB4 levels are reduced in AF patients. A mouse model of Erbb4 deficiency and human atrial transcriptomic analyses highlight a role for ERBB4 in supporting normal atrial metabolism while protecting against inflammation, apoptosis, and fibrosis.

[This corrects the article DOI: 10.7759/cureus.99405.].

Distal myopathies (DM) are clinically and genetically heterogeneous neuromuscular disorders, and identifying a molecular genetic cause may remain challenging in a subset of cases. Moreover, DM may be misdiagnosed as hereditary neuropathies due to overlapping clinical features. Here, we report a novel structural variant in FLNC associated with DM identified through genome sequencing (GS). Two affected relatives initially presented independently with referral diagnoses of Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. Clinical re-evaluation led to a change of the diagnosis to DM. Muscle MRI revealed a consistent pattern of selective muscle involvement characteristic of DM, enabling identification of six affected individuals within the family. GS was performed in seven family members, including six affected individuals and one unaffected relative. The analysis identified an insertion of two inverted fragments derived from the adjacent intron 2 into exon 3 of the FLNC gene. This complex rearrangement was accompanied by short non-templated nucleotide insertions at the junctions and a 3-bp exonic deletion at the insertion site, ultimately resulting in a frameshift. The structural variant was segregated with disease and was confirmed by Sanger sequencing and one Oxford nanopore long-read sequencing. Our findings expand the mutational spectrum of FLNC-associated disorders and highlight the importance of GS combined with a detailed clinical examination for the diagnosis of DM.

Dermatomyositis (DM) is an autoimmune inflammatory myopathy characterized by proximal muscle weakness and distinctive cutaneous manifestations. While dysphagia is a well-recognized otolaryngologic feature of DM, dysphonia-particularly as an early or isolated manifestation-remains under-recognized and may be overlooked, especially in professional voice users. Maria Callas, one of the most influential opera singers of the twentieth century, experienced a rapid and controversial vocal decline at the peak of her career, the etiology of which has long been debated.