Satoru Noguchi

Introduction/Aims: Valosin‐containing protein (VCP) myopathy is a rare multisystem disorder with variable clinical onset and progression. While region‐focused imaging studies have provided partial information on muscle involvement, how involvement is distributed across body regions and whether this pattern is characteristic remain unclear. We aimed to characterize disease‐specific spatial patterns of muscle involvement. Methods: Twelve patients from eleven unrelated families with genetically confirmed VCP myopathy underwent CT or T1‐weighted MRI. Fat replacement in 43 muscles across shoulder, trunk, pelvis, and lower limbs was graded using the modified Mercuri score (mMS). Uniform manifold approximation and projection (UMAP) dimensionality reduction and hierarchical clustering analyses identified characteristic patterns. Clinical correlations were assessed. Results: UMAP visualization of 43 muscles showed that VCP myopathy cases tended to occupy a relatively distinct region compared with other myopathies. Hierarchical clustering identified Mild ( n = 9) and Severe ( n = 3) groups, which differed significantly in total mMS ( p = 0.009). Both groups showed fatty replacement in trunk muscles (including iliocostalis lumborum, longissimus, and external abdominal oblique) and adductor magnus, with relative sparing of sternocleidomastoid, infraspinatus, subscapularis, trapezius, rhomboid, and rectus femoris. Substantial asymmetry occurred only when both sides were affected. Total mMS showed no correlation with age at imaging or disease duration. Discussion: This study demonstrates that VCP myopathy exhibits a characteristic pattern of muscle involvement on whole‐body multi‐region assessment. Although clinical heterogeneity was observed, consistently affected trunk muscles and adductor magnus, which may be involved early after symptom onset, may provide supportive imaging clues when VCP myopathy is suspected.

Introduction/Aims: DNM2 ‐related centronuclear myopathy ( DNM2 ‐CNM) exhibits characteristic imaging patterns, but imaging‐based staging and variant‐specific severity pattern remain incompletely defined. We aimed to (1) characterize muscle involvement patterns, (2) establish imaging‐based severity stages and identify muscles that best distinguish severity groups, and (3) model variant‐ and muscle‐specific age‐related score patterns, with comparison to adult‐onset MTM1 ‐related CNM. Methods: We retrospectively analyzed whole‐body muscle imaging (computed tomography/magnetic resonance imaging) in 30 genetically confirmed DNM2 ‐CNM patients. Forty‐five muscles were scored using the modified Mercuri score (mMs 0–4). Unsupervised uniform manifold approximation and projection (UMAP) and hierarchical clustering defined severity groups and involvement patterns. Violin plots characterized the distribution of mMs scores across severity stages. Linear regression and generalized additive models characterized variant and muscle‐specific age‐associated mMs patterns. Modal mMs values were used to generate comparative schematics for DNM2 ‐CNM and MTM1 ‐related CNM. Results: UMAP identified three severity groups. Hierarchical clustering revealed a distal‐predominant pattern with early severe involvement of posterior calf and paraspinal muscles, followed by posterior thigh and gluteal muscles. Variant modeling demonstrated distinct age‐associated mMs patterns: PH domain variants (A618T/S615L/S619L) showed earliest onset and steepest age‐associated rate of mMs increase (slope 10.1, p = 0.003), middle‐domain variants (E368K/R369G/R369Q) showed intermediate rate of mMs increase (slope 2.86), R465W was milder (slope 2.56), and R369W was slowest (slope 0.74). DNM2 ‐CNM showed distal‐to‐proximal involvement, contrasting with the proximal‐predominant pattern of MTM1 ‐related CNM. Discussion: Muscle imaging defines reproducible severity stages and variant‐specific age‐associated severity patterns, providing a quantitative imaging framework for DNM2 ‐CNM staging, monitoring, and risk stratification.

BACKGROUND: Although hyperthermia exacerbates the pathophysiology of malignant hyperthermia (MH), the response to hypothermia remains poorly understood. MH susceptible-swine studies suggested that hypothermia prevents MH, yet clinical cases occur during hypothermic cardiopulmonary bypass. This study aimed to elucidate whether hypothermia inhibits the MH trigger or merely decelerates the progression of the lethal metabolic cascade. METHODS: Pharmacological sensitivity of type 1 ryanodine receptor was evaluated in myotubes from heterozygous p.R2509C knock-in mice and wild-type (WT) mice by measuring the half-maximal effective concentration of caffeine at 30 °C and 40 °C. Intracellular calcium dynamics were also assessed during temperature changes. In vivo, anesthetized male and female mice were exposed to 2.5% sevoflurane at rectal temperatures of 34 °C or 36 °C. Survival time, heart rate, arterial blood gas analysis, and muscle ultrastructure were compared. RESULTS: Compared with WT myotubes, R2509C myotubes showed a leftward shift in the caffeine dose–response curve and a lower half-maximal effective concentration at both 30 °C (estimated treatment effects = 2.0 mM, 95% confidence interval [CI], 0.5–3.6 mM, P = .020) and 40 °C (estimated treatment effects = 2.1 mM, 95% CI, 0.5–3.7 mM, P = .029). Cooling myotubes from 36 °C to 34 °C significantly reduced relative intracellular Ca ^{2 +} fluorescence in R2509C myotubes. In vivo, all mutant mice developed MH and went into cardiac arrest regardless of temperature. Survival time was significantly longer at 34 °C compared to 36 °C (mean difference = 45.0 minutes, 95% CI, 20.9–69.1 minutes, P = .002). Typical signs such as tachycardia were absent at 34 °C. Despite masked clinical signs, progressive hypercapnia, metabolic acidosis, hyperkalemia, and characteristic mitochondrial swelling occurred in hypothermia. CONCLUSIONS: Hypothermia decelerates the clinical progression of MH but does not prevent triggering or lethality in mouse models. The caffeine-hypersensitivity of R2509C myotubes was detectable even under the lower-temperature assay condition. Mitochondrial swelling was identified as an ultra-early pathological change, suggesting that muscle damage is not solely driven by thermal injury. Clinicians should be aware that hypothermia may mask tachycardia and body temperature elevation, leaving hypercapnia and acidosis as critical early indicators.

Myotonic dystrophy type 1 is caused by the expression of expanded CTG repeats in the DMPK gene and the resulting loss of function of MBNL protein. Affected skeletal muscle displays abundant centrally located nuclei despite limited immune-cell–associated fibre necrosis, complicating interpretation of muscle damage and remodelling mechanisms. Here we show that muscle stem cells are activated and fuse with existing muscle fibres in myotonic dystrophy type 1. Single-nucleus transcriptomics in patient’s muscle identifies increased activated muscle stem cells and distinct myonuclear populations exhibiting transitional transcriptional states, including muscle stem cell associated markers and elevated DMPK expression. Myofibre-specific MBNL knockdown mouse models demonstrate that muscle stem cell fusion contributes to central nucleation, whereas their deletion does not improve myotonia or muscle strength. Together, these findings indicate that loss of MBNL function in muscle drives myonuclear accretion through stem cell-mediated fusion, giving rise to myonuclei with immature states in myotonic dystrophy type 1.

Caveolinopathies caused by CAV3 mutations present with heterogeneous clinical phenotypes ranging from asymptomatic hyperCKemia to limb-girdle–type muscular dystrophy. Although prior imaging studies have described commonly affected muscles, structured modeling of muscle involvement patterns in caveolinopathy has not been established. We analyzed whole-body skeletal muscle computed tomography imaging in eight patients with pathogenic or likely pathogenic CAV3 variants, comprising 14 imaging study samples. Fat infiltration across 43 muscles was graded using modified Mercuri scores. Computational multivariate analysis—including principal component analysis, clustering, and pseudotime modeling—was applied to characterize severity staging and distribution patterns. A statistically supported, stage-dependent continuum of muscle involvement was identified. Most samples demonstrated a distributed limb-girdle–predominant pattern with coordinated progression across muscle clusters. In contrast, one patient (three samples in longitudinal series) exhibited a compartment-restricted thigh-dominant pattern characterized by early posterior and medial thigh involvement. Rectus femoris showed consistent stage-dependent progression, while greater medial gastrocnemius involvement was associated with advanced severity. None of the patients exhibited clinical evidence of rippling muscle disease. These findings suggest that integrating semi-quantitative imaging with computational modeling may provide an objective framework for characterizing muscle involvement patterns in CAV3-related myopathy. Highlights: This is a whole-body muscle imaging analysis of caveolinopathy patients. Multivariate modeling was applied to CT-based modified Mercuri scores. Rectus femoris involvement may be useful as a progression indicator. Two distinct muscle involvement patterns were described. Greater medial gastrocnemius involvement may reflect more advanced disease.

Introduction/Aims: 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. Methods: 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. Results: 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. Discussion: 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.

Background and Purpose: Aberrant activation of type 2 ryanodine receptors (RyR2) causes lethal arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). Developing drugs that suppress RyR2 hyperactivation may be key to novel arrhythmia treatments. This study evaluated the antiarrhythmic potential of Ryanozole, a recently developed novel RyR2 modulator with high affinity and selectivity, using CPVT mouse models harbouring mutant RyR2s. Experimental Approach: In vitro effects of Ryanozole were evaluated by endoplasmic reticulum (ER) Ca ²⁺ ‐based assay and [ ³ H]ryanodine‐binding assay using RyR2‐expressing HEK293 cells. Two lines of mice with different arrhythmia severities, RyR2‐R420W and RyR2‐K4750Q, were employed for in vivo and ex vivo assessments. Intracellular Ca ²⁺ signals were analysed in isolated cardiomyocytes using Cal‐520. Antiarrhythmic effects were evaluated by electrocardiography (ECG) under catecholaminergic challenge in anaesthetized mice and during spontaneous arrhythmias in conscious mice. ECG and echocardiographic parameters were evaluated before and after drug administration. Key Results: Ryanozole inhibited both wild‐type and mutant RyR2s with an IC ₅₀ of 15–40 nM. Inhibition was more potent at lower cytosolic Ca ²⁺ concentrations. Ryanozole suppressed Ca ²⁺ waves and Ca ²⁺ sparks without affecting action potential‐evoked Ca ²⁺ transients. Ryanozole effectively prevented adrenaline‐induced arrhythmias and rapidly terminated ongoing spontaneous arrhythmias during daily activity. Importantly, Ryanozole did not impair cardiac conduction or contractility, unlike conventional antiarrhythmic drugs. Conclusion and Implications: Ryanozole preferentially suppresses RyR2 under diastolic Ca ²⁺ conditions, thereby preventing the arrhythmogenic trigger of aberrant Ca ²⁺ release. This mechanism may provide potent antiarrhythmic effects while preserving cardiac function. Ryanozole is a potential therapeutic candidate for RyR2‐mediated arrhythmias, such as CPVT.

Introduction/Aims: Variants in the SELENON gene cause a myopathy with axial weakness, scoliosis, and respiratory failure. This study aimed to characterize the temporal and spatial distribution of fat replacement across the whole body in patients with SELENON‐related myopathy. Methods: We conducted a retrospective study of genetically confirmed SELENON‐related myopathy patients at a single center who had available whole‐body skeletal muscle computed tomography or magnetic resonance imaging data. The degree of fat replacement in 47 skeletal muscles was scored using the modified Mercuri score (mMS). Spatial and temporal progression patterns of fat replacement were identified using k‐means clustering and hierarchical clustering. Results: The time‐series imaging data from a single patient revealed that muscles could be classified into four patterns: those showing fatty replacement from the initial stage, those that undergo fatty replacement in the early phases, those affected in the advanced stages, and those that show minimal fatty replacement throughout the disease course. In the early stage, fat replacement was most prominent in axial and hip girdle muscles. Subsequently, thigh muscles were affected. In contrast, the muscles of the arms and lower legs were preserved even in advanced‐stage patients. The whole‐body mMS increased linearly with age. No significant correlations were observed between the mMS and walking ability or respiratory function. Discussion: Fat replacement progresses with age, and serial imaging over time may allow more accurate prediction of muscle‐specific involvement. These data may be useful for monitoring disease progression and serve as potential biomarkers for future therapeutic interventions.

Oculopharyngodistal myopathy (OPDM) is a hereditary muscle disease caused by CGG/CCG repeat expansions in six genes. Although the clinical features are oft