Liewluck, Teerin

Abstract Objectives Medical nutrition therapy significantly impacts cardiovascular risk and overall health, but effects on muscle diseases remain unclear. This systematic review evaluates the safety and efficacy of dietary interventions and supplements on muscle disease outcomes. Methods A multidisciplinary team conducted a PRISMA-guided systematic review registered on PROSPERO. Searches were conducted across multiple databases and screened against pre-specified inclusion criteria. Results Of 107 full-text articles screened, 51 met inclusion criteria. Most identified interventions used dietary supplements rather than whole dietary approaches. In inflammatory myopathies, creatine (loading dose 20 g/day, maintenance 3 g/day) combined with exercise improved high-intensity functional performance in PM and DM over 6 months. In Duchenne muscular dystrophy, creatine (2–10 g/day for 8–16 weeks) improved maximal voluntary contraction and fatigue resistance. Carbohydrate-rich diets (65% CHO) reduced exercise-related symptoms in McArdle disease, while high-dose creatine (150 mg/kg/day) paradoxically worsened symptoms. Four trials of aceneuramic acid (6 g/day for 48 weeks) in GNE myopathy demonstrated dose-dependent strength improvements, leading to regulatory approval in Japan. High-protein supplementation showed positive trends for muscle preservation in critical illness myopathy. Quality assessment revealed 31% at low risk of bias, 49% with some concerns and 20% at high risk. Conclusion Evidence for nutritional interventions in muscle diseases remains limited, especially for inflammatory myopathies. The strongest support emerged for mechanistically targeted approaches: creatine with exercise, carbohydrate-rich and ketogenic diets in McArdle disease and sialic acid in GNE myopathy. Future research requires adequately powered multicentre trials with standardized outcomes, with focus on inflammatory myopathies.

ABSTRACT Background Monoclonal gammopathy‐associated myopathies (MGAMs) include light chain (AL) amyloid myopathy, sporadic late‐onset nemaline myopathy (SLONM), and vacuolar myopathy with monoclonal gammopathy and stiffness (VAMMGAS). These subtypes usually occur separately, although rare overlap has been described. We report a patient with monoclonal gammopathy and concurrent SLONM and excessive glycogen accumulation, resembling VAMMGAS but with distinct features. Methods Case report with clinical, electrophysiological, pathological, and therapeutic characterization of a patient with IgG‐kappa monoclonal gammopathy and coexisting SLONM and glycogen accumulation within muscle fibers. Results A 69‐year‐old man developed subacute progressive axial and limb weakness, head drop, dysphagia, and weight loss. Examination showed proximal/distal weakness, neck extensor weakness, and lumbar hyperlordosis. EMG revealed myopathic motor unit potentials without electrical myotonia or complex repetitive discharges. Serum studies identified IgG‐kappa monoclonal protein with elevated kappa light chain and ratio. Muscle biopsy demonstrated nemaline rods (1% of fibers) and scattered fibers with non‐rimmed vacuoles (0.3% of fibers) containing PAS‐positive, diastase‐labile material consistent with concurrent SLONM and glycogen storage myopathy‐like pathology. Genetic testing for congenital nemaline and glycogen storage myopathies was negative. Plasma‐cell directed therapy with daratumumab, lenalidomide, and dexamethasone led to rapid functional improvement and M‐protein reduction. Further gains followed autologous stem cell transplantation. Conclusion This case expands the MGAM spectrum, highlighting co‐occurrence of SLONM and an excessive glycogen accumulation responsive to immunotherapy and transplantation. These findings suggest a spectrum of related disease processes. Recognition of this combined pathology is clinically important, as affected patients may benefit from targeted immunotherapy or stem cell transplantation.

ABSTRACT Autoantibody internalization has been implicated in autoimmune disease pathogenesis, yet its mechanisms, and generality across different diseases, cell types, and affected tissues remain poorly defined. Using bulk RNA sequencing, we identified reproducible, autoantibody-specific transcriptomic signatures consistent with autoantigen dysfunction in muscle biopsies from patients with anti-Mi2 dermatomyositis and anti-PM/Scl scleromyositis across independent cohorts. Electroporation of purified patient IgG into primary cultures of healthy cells was sufficient to induce the corresponding transcriptomic programs in vitro . Direct immunofluorescence demonstrated immunoglobulin internalization into subcellular compartments matching the localization of the autoantigen in different affected tissues. Spatial transcriptomic analyses revealed that antibody-secreting cells translocated cytoplasmic material (i.e., immunoglobulin RNA) into adjacent affected cells expressing autoantibody-specific transcripts. The disease-specific transcripts were present not only in muscle fibers, but also in other cells, including macrophages, endothelial cells, and fibroblasts. Autoantibody-induced transcriptomic programs were associated with cell damage and autoantibody-specific reactive inflammatory programs, including activation of type I interferon and TGF-ß1 signaling in anti-Mi2 dermatomyositis and activation of type II interferon in anti-PM/Scl scleromyositis. Antibody internalization was also observed in different tissues from patients with other autoimmune diseases, including anti-U1RNP mixed connective tissue disease, anti-Ku overlap syndrome, and anti-Scl70 systemic sclerosis. Together, these findings establish autoantibody internalization as a shared pathogenic mechanism across diverse autoimmune diseases, providing a unifying framework for conditions driven by autoantibodies against intracellular antigens.

ABSTRACT Objectives T‐cell large granular lymphocytic leukemia (T‐LGLL), reported in up to 58% of inclusion body myositis (IBM) patients, is a rare leukemia of cytotoxic or less commonly helper T cells. The range of myopathies in T‐LGLL and the impact of coexisting T‐LGLL in IBM are not well understood. Our objectives are to investigate the spectrum of myopathies in patients with T‐LGLL and compare the clinical, serological, pathological, and transcriptomic features of IBM patients with and without T‐LGLL. Methods We reviewed two Mayo Clinic cohorts: (1) T‐LGLL patients evaluated for myopathies (2003–2018), and (2) IBM patients tested for T‐LGLL via T‐cell receptor gene rearrangement or flow cytometry (2016–2022). We also compared transcriptomic profiles of IBM muscle biopsies with and without T‐LGLL. Results Of 447 T‐LGLL patients, 13 (2.9%) had myopathies, IBM being the most common ( n = 7). Of 43 IBM patients, 9 (20.9%) had T‐LGLL, with 5 diagnosed prior to the onset of weakness. Clinical and pathological features were largely similar between IBM patients with and without T‐LGLL, except for milder finger flexor weakness and more frequent neutropenia (55.6% vs. 0%, p < 0.001) in the T‐LGLL group. However, transcriptomic analysis of muscle tissues revealed a more immunologically active profile, with upregulation of T‐cell and macrophage markers, elevated levels of IFN‐γ gene and IFN‐γ–inducible genes, heightened cytokine activity, and enhanced immunoglobulin production in IBM patients with T‐LGLL. Interpretation IBM is the most common myopathy in T‐LGLL patients. While clinico‐sero‐pathological features were largely similar, transcriptomic differences suggest IBM with T‐LGLL may represent a distinct, more immune‐driven subtype.

Abstract Objectives Granulomatous myositis (GM) is defined by focal collections of activated macrophages that fuse to form multinucleated cells that aggregate into granulomas within skeletal muscle. This study aimed to elucidate the pathophysiology of GM by defining its specific transcriptomic profile. Methods Bulk RNA sequencing was performed on 722 muscle biopsies, including 38 from patients with GM, other myopathies and healthy comparators. Spatial transcriptomics and immunohistochemistry assays were used to identify the location of specific transcripts and proteins within the tissue. Results We conducted a systematic analysis of the inflammatory pathways implicated in GM. This analysis revealed that GM muscle biopsies are characterized by elevated levels of IFNγ, IFNγ-inducible genes and proinflammatory cytokine genes including IL1B, TNF and TGFB1. Additionally, we identified a specific gene signature in GM, comprising 1293 genes that were significantly upregulated and 256 significantly downregulated. These genes were strongly correlated with transcriptomic markers of disease activity. Using this gene signature, support vector machine models accurately identified GM, achieving an area under the curve of 99.6% (99.0–99.9%) and an accuracy of 98.6% (98.2–98.9%). Among the identified genes, CHIT1 emerged as the most significantly upregulated gene, with its expression strongly correlating with disease severity. Furthermore, CHIT1 was detected at both the RNA and protein levels in granulomas and giant cells. Conclusion GM is transcriptomically characterized by a strong IFNγ signature and overexpression of proinflammatory cytokines, including IL1B, TNF and TGFB1. Additionally, it exhibits a unique transcriptomic profile, including CHIT1, which correlates with disease activity.

ABSTRACT Aims Sarcoid myopathy (SaM) is characterised by granulomatous myositis (GM) and can overlap with inclusion body myositis (IBM), a late‐onset chronic idiopathic inflammatory myopathy with a still enigmatic pathogenesis. As GM can occur in different clinical contexts, we aimed to examine the histomorphologic features and gene expression profiles in cases of definite SaM that may inform diagnostic and therapeutic considerations. Methods We performed a multidimensional characterisation of muscle biopsy specimens from patients with ‘pure SaM’ (n=17), SaM with concomitant IBM (SaM‐IBM) (n=2), including histopathologic and ultrastructural analysis in addition to quantitative real‐time polymerase chain reaction. Additionally, bulk RNA sequencing was performed on 38 muscle biopsy specimens from patients with SaM (including SaM‐IBM) (n=30) and NGI (n=8). Results Histopathological analysis revealed a pattern of endomysial and perimysial granulomatous inflammation frequently extending to the fascia, endomysial fibrosis, muscle fibre atrophy, variation in muscle fibre size and capillary thickening. Findings from immunohistochemical studies established Chitinase 1 as a pure giant cell marker in SaM. On a subcellular level, ‘pure SaM’ was characterised by focal accumulation of large swollen mitochondria with rare cristae but an absence of irregular cristae. Transcriptomic analysis of patients with SaM confirmed markedly elevated expression of both type 1 and type 2 human leukocyte antigen molecules. Macrophage activity markers were highly elevated. Consistent with histologic findings, CHIT1 was specifically overexpressed in SaM samples but not in ‘pure IBM’ muscle biopsy specimens. Conclusions SaM is characterised by a stereotypical appearance at the histopathologic level and disease‐specific immune dysregulation that involves macrophage function and maturation. SaM‐IBM represents a noteworthy overlap syndrome that shares multiple dysregulated immune pathways with ‘pure SaM’.