Effect of epicatechin consumption on the inflammatory pathway and mitochondria morphology in PBMC from a R350P desminopathy patient: A case report.

Desminopathy R350P is a human myopathy that is characterized by the progressive loss of muscle fiber organization. This results in the loss of muscle size, mobility, and strength. In desminopathy, inflammation affects muscle homeostasis and repair, and contributes to progressive muscle deterioration. Mitochondria morphology was also suggested to affect desminopathy progression. Epicatechin (Epi)-a natural compound found in cacao-has been proposed to regulate inflammatory signaling and mitochondria morphology in human and animal models. Hence, we hypothesize chronic Epi consumption to improve inflammatory pathway and mitochondria morphology in the peripheral blood mononuclear cells (PBMCs) of a desminopathy R350P patient. We found that 12 weeks of Epi consumption partially restored TRL4 signaling, indicative of inflammatory signaling and mitochondria morphology in the desminopathy patient. Moreover, Epi consumption improved blood health parameters, including reduced HOMA-IR and IL-6 levels in the desminopathy patient. This indicates that Epi consumption could be a useful tool to slow disease progression in desminopathy patients.

[Current and Future Status of Muscle Pathology: The Position of Muscle Pathology Diagnosis in the Future].

Many muscle disease names are mostly based on muscle pathology findings. Naturally, muscle pathology is important in the diagnosis of muscle diseases. Moreover, in recent years, extensive genetic analysis and autoantibody testing for myositis have been applied clinically, although muscle biopsies are less performed. However, muscle pathology should be proactively considered when a single gene presents multiple phenotypes, when variants of unknown pathological significance are detected, or in cases of autoimmune myositis that may be misdiagnosed as muscular dystrophy.

The structure and function of lamin A/C: Special focus on cardiomyopathy and therapeutic interventions.

Lamins are inner nuclear membrane proteins that belong to the intermediate filament family. Lamin A/C lie adjacent to the heterochromatin structure in polymer form, providing skeletal to the nucleus. Based on the localization, lamin A/C provides nuclear stability and cytoskeleton to the nucleus and modulates chromatin organization and gene expression. Besides being the structural protein making the inner nuclear membrane in polymer form, lamin A/C functions as a signalling molecule involved in gene expression as an enhancer inside the nucleus. Lamin A/C regulates various cellular pathways like autophagy and energy balance in the cytoplasm. Its expression is highly variable in differentiated tissues, higher in hard tissues like bone and muscle cells, and lower in soft tissues like the liver and brain. In muscle cells, including the heart, lamin A/C must be expressed in a balanced state. Lamin A/C mutation is linked with various diseases, such as muscular dystrophy, lipodystrophy, and cardiomyopathies. It has been observed that a good number of mutations in the LMNA gene impact cardiac activity and its function. Although several works have been published, there are still several unexplored areas left regarding the lamin A/C function and structure in the cardiovascular system and its pathological state. In this review, we focus on the structural organization, expression pattern, and function of lamin A/C, its interacting partners, and the pathophysiology associated with mutations in the lamin A/C gene, with special emphasis on cardiovascular diseases. With the recent finding on lamin A/C, we have summarized the possible therapeutic interventions to treat cardiovascular symptoms and reverse the molecular changes.

LMNA-related muscular dystrophy involving myoblast proliferation and apoptosis through the FOXO1/GADD45A pathway.

LMNA-related muscular dystrophy is a major disease phenotype causing mortality and morbidity in laminopathies, but its pathogenesis is still unclear. To explore the molecular pathogenesis, a knock-in mouse harbouring the Lmna-W520R mutation was modelled. Morphological and motor functional analyses showed that homozygous mutant mice revealed severe muscular atrophy, profound motor dysfunction, and shortened lifespan, while heterozygotes showed a variant arrangement of muscle bundles and mildly reduced motor capacity. Mechanistically, the FOXO1/GADD45A pathway involving muscle atrophy processes was found to be altered in vitro and in vivo assays. The expression levels of FOXO1 and its downstream regulatory molecule GADD45A significantly increased in atrophic muscle tissue. The elevated expression of FOXO1 was associated with decreased H3K27me3 in its gene promotor region. Overexpression of GADD45A induced apoptosis and cell cycle arrest of myoblasts in vitro, and it could be partially restored by the FOXO1 inhibitor AS1842856, which also slowed the muscle atrophy process with improved motor function and prolonged survival time of homozygous mutant mice in vivo. Notably, the inhibitor also partly rescued the apoptosis and cell cycle arrest of hiPSC-derived myoblasts harbouring the LMNA-W520R mutation. Together, these data suggest that the activation of the FOXO1/GADD45A pathway contributes to the pathogenesis of LMNA-related muscle atrophy, and it might serve as a potential therapeutic target for laminopathies.

CGG repeat expansion in LOC642361/NUTM2B-AS1 typically presents as oculopharyngodistal myopathy.

CGG repeat expansions in LOC642361/NUTM2B-AS1 have recently been identified as a cause of oculopharyngeal myopathy with leukoencephalopathy. However, since only three patients from a single family were reported, it remains unknown whether their clinicopathological features are typical for CGG repeat expansions in LOC642361/NUTM2B-AS1. Here, using repeat-primed-polymerase chain reaction and long-read sequencing, we identify 12 individuals from 3 unrelated families with CGG repeat expansions in LOC642361/NUTM2B-AS1, typically presenting with oculopharyngodistal myopathy. The CGG repeat expansions range from 161 to 669 repeat units. Most of the patients present with ptosis, restricted eye movements, dysphagia, dysarthria, and diffuse limb muscle weakness. Only one patient shows T2-weighted hyperintensity in the cerebellar white matter surrounding the deep cerebellar nuclei on brain magnetic resonance imaging. Muscle biopsies from three patients show a myopathic pattern and rimmed vacuoles. Analyses of muscle biopsies suggest that CGG repeat expansions in LOC642361/NUTM2B-AS1 may deleteriously affect aggrephagic capacity, suggesting that RNA toxicity and mitochondrial dysfunction may contribute to pathogenesis. Our study thus expands the phenotypic spectrum for the CGG repeat expansion of LOC642361/NUTM2B-AS1 and indicates that this genetic variant typically manifests as oculopharyngodistal myopathy with chronic myopathic changes with rimmed vacuoles and filamentous intranuclear inclusions in muscle fibers.

Intrafamilial phenotypic heterogeneity in GIPC1-related oculopharyngodistal myopathy type 2: a case report.

Oculopharyngodistal myopathy (OPDM) is a rare adult-onset neuromuscular disease characterized by ocular, facial, bulbar and distal limb muscle weakness. Here, we presented a pair of siblings with OPDM2 displaying marked intrafamilial phenotypic heterogeneity. In addition to muscle weakness, the proband also demonstrated tremor and visual disturbance that have not been reported previously in OPDM2. Electrophysiological and pathological studies further suggested the presence of neurogenic impairment in the proband. Repeat-primed polymerase chain reaction (RP-PCR) and fluorescence amplicon length analysis polymerase chain reaction (AL-PCR) confirmed the molecular diagnosis of OPDM2 in the siblings. Given the rarity of the case, the association between OPDM2 and tremor, visual disturbance, or neurogenic impairment remained to be explored.

Megaconial congenital muscular dystrophy due to CHKB gene variants, the first report of thirteen Iranian patients.

Megaconial congenital muscular dystrophy (OMIM: 602,541) related to CHKB gene mutation is a newly defined rare autosomal recessive disorder, with multisystem involvement presenting from the neonatal period to adolescence. Choline kinase beta, lipid transport enzyme, catalyzes the biosynthesis of phosphatidylcholine and phosphatidylethanolamine, two major components of the mitochondrial membrane, on which respiratory enzyme activities are dependent. CHKB gene variants lead to loss-of-function of choline kinase b and lipid metabolism defects and mitochondrial structural changes. To date, many megaconial congenital muscular dystrophy cases due to CHKB gene variants have been reported worldwide. We describe thirteen Iranian megaconial congenital muscular dystrophy cases related to CHKB gene variants, including clinical presentations, laboratory and muscle biopsy findings, and novel CHKB gene variants. The most common symptoms and signs included intellectual disability, delayed gross-motor developmental milestones, language skills problems, muscle weakness, as well as autistic features, and behavioral problems. Muscle biopsy examination showed the striking finding of peripheral arrangements of large mitochondria in muscle fibers and central sarcoplasmic areas devoid of mitochondria. Eleven different CHKB gene variants including six novel variants were found in our patients. Despite the rarity of this disorder, recognition of the multisystem clinical presentations combined with characteristic findings of muscle histology can properly guide to genetic evaluation of CHKB gene.

Muscle MRI in periodic paralysis shows myopathy is common and correlates with intramuscular fat accumulation.

INTRODUCTION/AIMS: The periodic paralyses are muscle channelopathies: hypokalemic periodic paralysis (CACNA1S and SCN4A variants), hyperkalemic periodic paralysis (SCN4A variants), and Andersen-Tawil syndrome (KCNJ2). Both episodic weakness and disabling fixed weakness can occur. Little literature exists on magnetic resonance imaging (MRI) in muscle channelopathies. We undertake muscle MRI across all subsets of periodic paralysis and correlate with clinical features. METHODS: A total of 45 participants and eight healthy controls were enrolled and underwent T1-weighted and short-tau-inversion-recovery (STIR) MRI imaging of leg muscles. Muscles were scored using the modified Mercuri Scale. RESULTS: A total of 17 patients had CACNA1S variants, 16 SCN4A, and 12 KCNJ2. Thirty-one (69%) had weakness, and 9 (20%) required a gait-aid/wheelchair. A total of 78% of patients had intramuscular fat accumulation on MRI. Patients with SCN4A variants were most severely affected. In SCN4A, the anterior thigh and posterior calf were more affected, in contrast to the posterior thigh and posterior calf in KCNJ2. We identified a pattern of peri-tendinous STIR hyperintensity in nine patients. There were moderate correlations between Mercuri, STIR scores, and age. Intramuscular fat accumulation was seen in seven patients with no fixed weakness. DISCUSSION: We demonstrate a significant burden of disease in patients with periodic paralyses. MRI intramuscular fat accumulation may be helpful in detecting early muscle involvement, particularly in those without fixed weakness. Longitudinal studies are needed to assess the role of muscle MRI in quantifying disease progression over time and as a potential biomarker in clinical trials.

Differential histological features and myogenic protein levels in distinct muscles of d-sarcoglycan null muscular dystrophy mouse model.

Skeletal muscle (SkM) comprises slow and fast-twitch fibers, which differ in molecular composition, function, and systemic energy consumption. In addition, muscular dystrophies (DM), a group of diverse hereditary diseases, present different patterns of muscle involvement, progression, and severity, suggesting that the regeneration-degeneration process may differ depending on the muscle type. Therefore, the study aimed to explore the expression of proteins involved in the repair process in different muscles at an early stage of muscular dystrophy in the δ-sarcoglycan null mice (Sgcd-null), a limb-girdle muscular dystrophy 2 F model. Hematoxylin & Eosin (H&E) Staining showed a high number of central nuclei in soleus (Sol), tibialis (Ta), gastrocnemius (Gas), and extensor digitorum longus (Edl) from four months Sgcd-null mice. However, fibrosis, determined by trichrome of Gomori modified staining, was only observed in Sgcd-null Sol. In addition, the number of Type I and II fibers variated differentially in the Sgcd-null muscles vs. wild-type muscles. Besides, the protein expression level of ß-catenin, myomaker, MyoD, and myogenin also presented different expression levels in all the Sgcd-null muscles studied. In summary, our study reveals that muscles with different metabolic characteristics showed distinct expression patterns of proteins involved in the muscle regeneration process. These results could be relevant in designing therapies for genetic and acquired myopathy.

Histopathological correlations and fat replacement imaging patterns in recessive limb-girdle muscular dystrophy type 12.

BACKGROUND: Despite the widespread use of proton density fat fraction (PDFF) measurements with magnetic resonance imaging (MRI) to track disease progression in muscle disorders, it is still unclear how these findings relate to histopathological changes in muscle biopsies of patients with limb-girdle muscular dystrophy autosomal recessive type 12 (LGMDR12). Furthermore, although it is known that LGMDR12 leads to a selective muscle involvement distinct from other muscular dystrophies, the spatial distribution of fat replacement within these muscles is unknown. METHODS: We included 27 adult patients with LGMDR12 and 27 age-matched and sex-matched healthy controls and acquired 6-point Dixon images of the thighs and T1 and short tau inversion recovery (STIR) MR images of the whole body. In 16 patients and 15 controls, we performed three muscle biopsies, one in the semimembranosus, vastus lateralis, and rectus femoris muscles, which are severely, intermediately, and mildly affected in LGMDR12, respectively. We correlated the PDFF to the fat percentage measured on biopsies of the corresponding muscles, as well as to the Rochester histopathology grading scale. RESULTS: In patients, we demonstrated a strong correlation of PDFF on MRI and muscle biopsy fat percentage for the semimembranosus (r = 0.85, P < 0.001) and vastus lateralis (r = 0.68, P = 0.005). We found similar results for the correlation between PDFF and the Rochester histopathology grading scale. Out of the five patients with inflammatory changes on muscle biopsy, three showed STIR hyperintensities in the corresponding muscle on MRI. By modelling the PDFF on MRI for 18 thigh muscles from origin to insertion, we observed a significantly inhomogeneous proximo-distal distribution of fat replacement in all thigh muscles of patients with LGMDR12 (P < 0.001), and different patterns of fat replacement within each of the muscles. CONCLUSIONS: We showed a strong correlation of fat fraction on MRI and fat percentage on muscle biopsy for diseased muscles and validated the use of Dixon fat fraction imaging as an outcome measure in LGMDR12. The inhomogeneous fat replacement within thigh muscles on imaging underlines the risk of analysing only samples of muscles instead of the entire muscles, which has important implications for clinical trials.

Estimating the Prevalence of LAMA2 Congenital Muscular Dystrophy using Population Genetic Databases.

BACKGROUND: Recessive pathogenic variants in LAMA2 resulting in complete or partial loss of laminin α2 protein cause congenital muscular dystrophy (LAMA2 CMD). The prevalence of LAMA2 CMD has been estimated by epidemiological studies to lie between 1.36-20 cases per million. However, prevalence estimates from epidemiological studies are vulnerable to inaccuracies owing to challenges with studying rare diseases. Population genetic databases offer an alternative method for estimating prevalence. OBJECTIVE: We aim to use population allele frequency data for reported and predicted pathogenic variants to estimate the birth prevalence of LAMA2 CMD. METHODS: A list of reported pathogenic LAMA2 variants was compiled from public databases, and supplemented with predicted loss of function (LoF) variants in the Genome Aggregation Database (gnomAD). gnomAD allele frequencies for 273 reported pathogenic and predicted LoF LAMA2 variants were used to calculate disease prevalence using a Bayesian methodology. RESULTS: The world-wide birth prevalence of LAMA2 CMD was estimated to be 8.3 per million (95% confidence interval (CI) 6.27 -10.5 per million). The prevalence estimates for each population in gnomAD varied, ranging from 1.79 per million in East Asians (95% CI 0.63 -3.36) to 10.1 per million in Europeans (95% CI 6.74 -13.9). These estimates were generally consistent with those from epidemiological studies, where available. CONCLUSIONS: We provide robust world-wide and population-specific birth prevalence estimates for LAMA2 CMD, including for non-European populations in which LAMA2 CMD prevalence hadn't been studied. This work will inform the design and prioritization of clinical trials for promising LAMA2 CMD treatments.

Collagen VI in the Musculoskeletal System.

Collagen VI exerts several functions in the tissues in which it is expressed, including mechanical roles, cytoprotective functions with the inhibition of apoptosis and oxidative damage, and the promotion of tumor growth and progression by the regulation of cell differentiation and autophagic mechanisms. Mutations in the genes encoding collagen VI main chains, COL6A1, COL6A2 and COL6A3, are responsible for a spectrum of congenital muscular disorders, namely Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM) and myosclerosis myopathy (MM), which show a variable combination of muscle wasting and weakness, joint contractures, distal laxity, and respiratory compromise. No effective therapeutic strategy is available so far for these diseases; moreover, the effects of collagen VI mutations on other tissues is poorly investigated. The aim of this review is to outline the role of collagen VI in the musculoskeletal system and to give an update about the tissue-specific functions revealed by studies on animal models and from patients' derived samples in order to fill the knowledge gap between scientists and the clinicians who daily manage patients affected by collagen VI-related myopathies.

The bi-directional relationship between sleep and inflammation in muscular dystrophies: A narrative review.

Muscular dystrophies vary in presentation and severity, but are associated with profound disability in many people. Although characterised by muscle weakness and wasting, there is also a very high prevalence of sleep problems and disorders which have significant impacts on quality of life in these individuals. There are no curative therapies for muscular dystrophies, with the only options for patients being supportive therapies to aid with symptoms. Therefore, there is an urgent need for new therapeutic targets and a greater understanding of pathogenesis. Inflammation and altered immunity are factors which have prominent roles in some muscular dystrophies and emerging roles in others such as type 1 myotonic dystrophy, signifying a link to pathogenesis. Interestingly, there is also a strong link between inflammation/immunity and sleep. In this review, we will explore this link in the context of muscular dystrophies and how it may influence potential therapeutic targets and interventions.

A single dose of exercise stimulates skeletal muscle mitochondrial plasticity in myotonic dystrophy type 1.

AIM: Myotonic dystrophy type 1 (DM1) is the second most common muscular dystrophy after Duchenne and is the most prevalent muscular dystrophy in adults. DM1 patients that participate in aerobic exercise training experience several physiological benefits concomitant with improved muscle mitochondrial function without alterations in typical DM1-specific disease mechanisms, which suggests that correcting organelle health is key to ameliorate the DM1 pathology. However, our understanding of the molecular mechanisms of mitochondrial turnover and dynamics in DM1 skeletal muscle is lacking. METHODS: Skeletal muscle tissue was sampled from healthy and DM1 mice under sedentary conditions and at several recovery time points following an exhaustive treadmill run. RESULTS: We demonstrate that DM1 patients exhibit an imbalance in the transcriptional apparatus for mitochondrial turnover and dynamics in skeletal muscle. Additionally, DM1 mice displayed elevated expression of autophagy and mitophagy regulators. A single dose of exercise successfully enhanced canonical exercise molecular pathways and skeletal muscle mitochondrial biogenesis despite failing to alter the cellular pathology in DM1 mice. However, treadmill running stimulated coordinated organelle fusion and fission signaling, as well as improved alternative splicing of Optic atrophy 1. Exercise also evoked autophagy and mitophagy pathways in DM1 skeletal muscle resulting in the normalized expression of autophagy- and lysosome-related machinery responsible for the clearance of dysfunctional organelles. CONCLUSION: Collectively, our data indicate that mitochondrial dynamics and turnover processes in DM1 skeletal muscle are initiated with a single dose of exercise, which may underlie the adaptive benefits previously documented in DM1 mice and patients.

The role of magnetic resonance imaging in the diagnostic work-out of myopathies: differential diagnosis between inflammatory myopathies and muscular dystrophies.

OBJECTIVES: The differential diagnosis between idiopathic inflammatory myopathies (IIM) and muscular dystrophies (MD) may be challenging. We analysed the potential role of muscular magnetic resonance imaging (MRI) in the differential diagnosis between IIM and MD. METHODS: MRI of patients (91 IIM and 43 MD), studied with a standardised protocol, have been collected. The presence of oedema, muscular atrophy and intramuscular adipose changes were evaluated. Moreover, we computed a composite score for each MRI item to better discriminate between the two diseases. RESULTS: Oedema was significantly more prevalent in IIM compared with MD in pelvis muscles (p<0.001), anterior lodge and medial lodges (p=0.044) of the thighs. Adipose infiltration/substitution and muscular atrophy were more prevalent in MD, in particular adipose tissue was prevalent in all the compartments of the thighs (p<0.05), atrophy was prevalent at the thighs and pelvis muscles (p<0.001). The probability of IIM increased with higher oedema score and decreased with higher atrophy and intramuscular adipose infiltration/substitution scores. CONCLUSIONS: A different distribution of muscular involvement between IIM and MD has been identified. Muscular MRI may be useful in the differential diagnosis, potentially reducing the number of muscular biopsies that may be reserved only for doubtful cases.

Radiographic, MRI, and CT findings in a young dog with Becker-like muscular dystrophy.

An 8-month-old, male, crossbreed dog was presented for macroglossia, reduced mandibular extension, ptyalism, dysphagia, and regurgitation. Serum creatine kinase and aspartate aminotransferase activity were markedly increased. Thoracic radiographs showed an axial gastro-esophageal hiatal hernia, diaphragmatic thickening, and asymmetry. Magnetic resonance imaging of the head showed a severely enlarged tongue, symmetric increase in size of the geniohyoid and mylohyoid muscles, and diffuse masticatory hypomyotrophy. Whole-body CT ruled out other musculoskeletal abnormalities and further characterized the radiographic and MRI findings. Muscular histopathology was consistent with Becker muscular dystrophy.

Current Strategies of Muscular Dystrophy Therapeutics: An Overview.

Muscular dystrophies are a group of genetic disorders characterized by varying degrees of progressive muscle weakness and degeneration. They are clinically and genetically heterogeneous but share the common histological features of dystrophic muscle. There is currently no cure for muscular dystrophies, which is of particular concern for the more disabling and/or lethal forms of the disease. Through the years, several therapies have encouragingly been developed for muscular dystrophies and include genetic, cellular, and pharmacological approaches. In this chapter, we undertake a comprehensive exploration of muscular dystrophy therapeutics under current development. Our review includes antisense therapy, CRISPR, gene replacement, cell therapy, nonsense suppression, and disease-modifying small molecule compounds.

Dystrophin-Deficient Muscular Dystrophy in Two Male Juvenile Brittanys.

A 6 mo old and a 7 mo old male intact Brittany were presented for progressive exercise intolerance, failure to grow, and dysphagia. Creatine kinase activity was markedly and persistently elevated in both dogs. Based on the neurological examination, clinical signs localized to the neuromuscular system. Electromyography revealed complex repetitive discharges in multiple muscle groups. Immunofluorescence of biopsies confirmed dystrophin-deficient muscular dystrophy. This is the first report describing dystrophin-deficient muscular dystrophy in the Brittany breed. Currently, no specific therapies are available for this form of myopathy. The presence of dystrophin deficiency in the two dogs suggests an inherited myopathy rather than a spontaneous mutation. The location of the dogs in the United States and Japan suggests a wide distribution of this dystrophy and should alert clinicians to the existence of this myopathy in the Brittany breed. A mutation in the DMD gene has not yet been identified.

Transcriptomic profiles of muscular dystrophy with myositis (mdm) in extensor digitorum longus, psoas, and soleus muscles from mice.

BACKGROUND: Titinopathies are inherited muscular diseases triggered by genetic mutations in the titin gene. Muscular dystrophy with myositis (mdm) is one such disease caused by a LINE repeat insertion, leading to exon skipping and an 83-amino acid residue deletion in the N2A-PEVK region of mouse titin. This region has been implicated in a number of titin-titin ligand interactions, hence are important for myocyte signaling and health. Mice with this mdm mutation develop a severe and progressive muscle degeneration. The range of phenotypic differences observed in mdm mice shows that the deletion of this region induces a cascade of transcriptional changes extending to numerous signaling pathways affected by the titin filament. Previous research has focused on correlating phenotypic differences with muscle function in mdm mice. These studies have provided understanding of the downstream physiological effects resulting from the mdm mutation but only provide insights on processes that can be physiologically observed and measured. We used differential gene expression (DGE) to compare the transcriptomes of extensor digitorum longus (EDL), psoas and soleus muscles from wild-type and mdm mice to develop a deeper understand of these tissue-specific responses. RESULTS: The overall expression pattern observed shows a well-differentiated transcriptional signature in mdm muscles compared to wild type. Muscle-specific clusters observed within the mdm transcriptome highlight the level of variability of each muscle to the deletion. Differential gene expression and weighted gene co-expression network analysis showed a strong directional response in oxidative respiration-associated mitochondrial genes, which aligns with the poor shivering and non-shivering thermogenesis previously observed. Sln, which is a marker associated with shivering and non-shivering thermogenesis, showed the strongest expression change in fast-fibered muscles. No drastic changes in MYH expression levels were reported, which indicated an absence of major fiber-type switching events. Overall expression shifts in MYH isoforms, MARPs, and extracellular matrix associated genes demonstrated the transcriptional complexity associated with mdm mutation. The expression alterations in mitochondrial respiration and metabolism related genes in the mdm muscle dominated over other transcriptomic changes, and likely account for the late stage cellular responses in the mdm muscles. CONCLUSIONS: We were able to demonstrate that the complex nature of mdm mutation extends beyond a simple rearrangement in titin gene. EDL, psoas and soleus exemplify unique response modes observed in skeletal muscles with mdm mutation. Our data also raises the possibility that failure to maintain proper energy homeostasis in mdm muscles may contribute to the pathogenesis of the degenerative phenotype in mdm mice. Understanding the full disease-causing molecular cascade is difficult using bulk RNA sequencing techniques due to intricate nature of the disease. The development of the mdm phenotype is temporally and spatially regulated, hence future studies should focus on single fiber level investigations.

Water T2 could predict functional decline in patients with dysferlinopathy.

BACKGROUND: Water T2 (T2H2O ) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2H2O to identify changes in muscle function over time in limb girdle muscular dystrophies. METHODS: Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3-tesla magnetic resonance imaging (MRI) systems from the same vendor. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration, and baseline function. RESULTS: A higher T2H2O at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2H2O in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2H2O (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6-min walk than those with a lower T2H2O (<40.6 ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0 ms in adductor magnus and vastus intermedius, 40.0 ms in vastus medialis, and 40.5 ms in vastus lateralis from different sites equipped with different MRI systems. CONCLUSIONS: In dysferlinopathy, T2H2O did not correlate with current functional ability. However, T2H2O at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter-patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2H2O measure at baseline. Significant challenges remain in standardizing T2H2O values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2H2O could be used to improve prognostication, patient selection, and disease modelling for clinical trials.