Genetic Muscle Disorders Research Articles

Ion Mobility QTOF-MS Untargeted Lipidomics of Human Serum Reveals a Metabolic Fingerprint for GNE Myopathy.

GNE myopathy, also known as hereditary inclusion body myopathy (HIBM), is a rare genetic muscle disorder marked by a gradual onset of muscle weakness in young adults. GNE myopathy (GNEM) is caused by bi-allelic variants in the UDP-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase)/N-acetylmannosamine kinase (ManNAc kinase) gene (GNE), clinically resulting in the loss of ambulation within 10-20 years from the onset of the initial symptoms. The disease's mechanism is poorly understood and non-invasive biomarkers are lacking, hindering effective therapy development. Based on the available evidence, we employed a lipidomic approach to study the serum lipid profile of GNE patients. The multivariate statistical analysis revealed a downregulation of carnitines, as well as of lysophosphatidylcholines, in sera samples derived from GNEM patients. Furthermore, we identified lower levels of sphingomyelins and, concomitantly, high levels of ceramides in serum samples from GNEM patients when compared to control samples derived from healthy donors. Moreover, the GNEM serum samples showed the upregulation of Krebs cycle intermediates, in addition to a decrease in oxaloacetic acid. The correlated data gathered in this study can offer a promising diagnostic panel of complex lipids and polar metabolites that can be used in clinic for GNEM in terms of a metabolic fingerprint measurable in a minimally invasive manner.

Protein redistribution in buccal cells as a prognostic marker for arrhythmogenic cardiomyopathy in paediatric patients

Abstract Background Mutations in genes encoding desmosomal proteins [plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2) and desmocollin-2 (DSC2)] cause complex genetic heart muscle disorders collectively described as arrhythmogenic cardiomyopathies (ACM). Diagnosis and risk stratification, particularly in the paediatric population, remain challenging owing to heterogeneous phenotypic manifestations and reduced genetic penetrance. Immunohistochemical analysis of heart muscle samples has shown that several junctional and signalling molecules are redistributed in patients with ACM, offering diagnostic information. However, the use of this approach in living patients was limited by need for heart samples. Recent studies in adults with ACM showed that the same set of proteins re-localised in the ACM heart also do so in the buccal epithelium. Purpose Given the ease of analysing serial cheek smears, we sought to establish how protein redistribution in buccal cells relates to disease onset and progression in children bearing desmosomal gene mutations. Methods Serial cheek smears from children with desmosomal variants were subjected to immunocytochemistry and confocal microscopy to study the distribution of JUP, DSP and PKP-1 as well as the major gap junction protein connexin43 (Cx43; GJA1) and the major subunit of the NFκB inflammatory pathway; RelA. Results 37 patients Conclusion These data indicate that shifts in junctional/signalling proteins precede the onset of clinical disease. Indeed, in the majority of pre-clinical children, Cx43 and RelA seem to be redistributed first, suggesting that onset of abnormalities in electrical conductivity and inflammatory pathways occur first in the natural disease progression, in agreement with previous clinical observations. Moreover, the data suggest that additional proteins are shifted as the disease progresses. Although further verification is required, this study suggests that analysis of buccal smears may be used as a prognostic/risk stratification test in children with desmosomal variants.

Organoid culture promotes dedifferentiation of mouse myoblasts into stem cells capable of complete muscle regeneration.

Experimental cell therapies for skeletal muscle conditions have shown little success, primarily because they use committed myogenic progenitors rather than true muscle stem cells, known as satellite cells. Here we present a method to generate in vitro-derived satellite cells (idSCs) from skeletal muscle tissue. When transplanted in small numbers into mouse muscle, mouse idSCs fuse into myofibers, repopulate the satellite cell niche, self-renew, support multiple rounds of muscle regeneration and improve force production on par with freshly isolated satellite cells in damaged skeletal muscle. We compared the epigenomic and transcriptional signatures between idSCs, myoblasts and satellite cells and used these signatures to identify core signaling pathways and genes that confer idSC functionality. Finally, from human muscle biopsies, we successfully generated satellite cell-like cells in vitro. After further development, idSCs may provide a scalable source of cells for the treatment of genetic muscle disorders, trauma-induced muscle damage and age-related muscle weakness.

Overview of epidemiology and management hypertrophic cardiomyopathy among children

Hypertrophic cardiomyopathy is the most common form of cardiomyopathy. It is a heterogeneous genetic cardiac muscle disorder characterized by inappropriate left ventricular hypertrophy, malalignment of the myocardial fibers, and myocardial fibrosis.

The Clinical Development of Taldefgrobep Alfa: An Anti-Myostatin Adnectin for the Treatment of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a genetic muscle disorder that manifests during early childhood and is ultimately fatal. Recently approved treatments targeting the genetic cause of DMD are limited to specific subpopulations of patients, highlighting the need for therapies with wider applications. Pharmacologic inhibition of myostatin, an endogenous inhibitor of muscle growth produced almost exclusively in skeletal muscle, has been shown to increase muscle mass in several species, including humans. Taldefgrobep alfa is an anti-myostatin recombinant protein engineered to bind to and block myostatin signaling. Preclinical studies of taldefgrobep alfa demonstrated significant decreases in myostatin and increased lower limb volume in three animal species, including dystrophic mice. This manuscript reports the cumulative data from three separate clinical trials of taldefgrobep alfa in DMD: a phase1 study in healthy adult volunteers (NCT02145234), and two randomized, double-blind, placebo-controlled studies in ambulatory boys with DMD-a phase1b/2 trial assessing safety (NCT02515669) and a phase2/3 trial including the North Star Ambulatory Assessment (NSAA) as the primary endpoint (NCT03039686). In healthy adult volunteers, taldefgrobep alfa was generally well tolerated and resulted in a significant increase in thigh muscle volume. Treatment with taldefgrobep alfa was associated with robust dose-dependent suppression of free myostatin. In the phase1b/2 trial, myostatin suppression was associated with a positive effect on lean body mass, though effects on muscle mass were modest. The phase2/3 trial found that the effects of treatment did not meet the primary endpoint pre-specified futility analysis threshold (change from baseline of ≥ 1.5 points on the NSAA total score). The futility analysis demonstrated that taldefgrobep alfa did not result in functional change for boys with DMD. The program was subsequently terminated in 2019. Overall, there were no safety concerns, and no patients were withdrawn from treatment as a result of treatment-related adverse events or serious adverse events. NCT02145234, NCT02515669, NCT03039686.

Raised CK and acute kidney injury following intense exercise in three patients with a history of exercise intolerance due to homozygous mutations in SLC2A9

Acute rhabdomyolysis (AR) leading to acute kidney injury has many underlying etiologies, however, when the primary trigger is exercise, the most usual underlying cause is either a genetic muscle disorder or unaccustomed intense exercise in a healthy individual. Three adult men presented with a history of exercise intolerance and episodes of acute renal impairment following intense exercise, thought to be due to AR in the case of two, and dehydration in one. The baseline serum CK was mildly raised between attacks in all three patients and acutely raised during attacks in two of the three patients. Following referral to a specialized neuromuscular centre, further investigation identified very low serum urate (<12 umol/L). In all three men, genetic studies confirmed homozygous mutations in SLC2A9, which encodes for facilitated glucose transporter member 9 (GLUT9), a major regulator of urate homeostasis. Hereditary hypouricaemia should be considered in people presenting with acute kidney injury related to intense exercise. Serum urate evaluation is a useful screening test best undertaken after recovery.

Generation of a homozygous CRYAB p.Arg120Gly mutant (UKEi001-A-1) from a human iPSC line

Variants in CRYAB can lead to desmin-related (cardio-)myopathy (DRM), a genetic muscle disorder with no curative treatment available. We introduced a homozygous CRYAB c.358G > A (p.Arg120Gly) mutation, which is established for the study of DRM in mice, into a donor human induced pluripotent stem cell (hiPSC) line. Control and mutant hiPSCs were tested for karyotype integrity and pluripotency marker expression. HiPSCs could be differentiated into endoderm, ectoderm and cardiomyocytes as a mesodermal derivative in vitro. CRYABhom hiPSC-derived cardiomyocytes developed intracellular CRYAB aggregates, which is a hallmark of DRM. This newly created mutant can be utilized to study DRM and cardiac proteinopathy in a human context.

Abnormal myosin post-translational modifications and ATP turnover time associated with human congenital myopathy-related RYR1 mutations.

Conditions related to mutations in the gene encoding the skeletal muscle ryanodine receptor 1 (RYR1) are genetic muscle disorders and include congenital myopathies with permanent weakness, as well as episodic phenotypes such as rhabdomyolysis/myalgia. Although RYR1 dysfunction is the primary mechanism in RYR1-related disorders, other downstream pathogenic events are less well understood and may include a secondary remodeling of major contractile proteins. Hence, in the present study, we aimed to investigate whether congenital myopathy-related RYR1 mutations alter the regulation of the most abundant contractile protein, myosin. We used skeletal muscle tissues from five patients with RYR1-related congenital myopathy and compared those with five controls and five patients with RYR1-related rhabdomyolysis/myalgia. We then defined post-translational modifications on myosin heavy chains (MyHCs) using LC/MS. In parallel, we determined myosin relaxed states using Mant-ATP chase experiments and performed molecular dynamics (MD) simulations. LC/MS revealed two additional phosphorylations (Thr1309-P and Ser1362-P) and one acetylation (Lys1410-Ac) on the β/slow MyHC of patients with congenital myopathy. This method also identified six acetylations that were lacking on MyHC type IIa of these patients (Lys35-Ac, Lys663-Ac, Lys763-Ac, Lys1171-Ac, Lys1360-Ac, and Lys1733-Ac). MD simulations suggest that modifying myosin Ser1362 impacts the protein structure and dynamics. Finally, Mant-ATP chase experiments showed a faster ATP turnover time of myosin heads in the disordered-relaxed conformation. Altogether, our results suggest that RYR1 mutations have secondary negative consequences on myosin structure and function, likely contributing to the congenital myopathic phenotype.

Long-read Nanopore sequencing identified D4Z4 contractions in patients with facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disorder caused by abnormal expression of the DUX4 protein, commonly resulting from a contraction of D4Z4 repeat units with the presence of a polyadenylation (polyA) signal. More than 10 units of the D4Z4 repeat, with a length of 3.3 kb per unit, are typically required to silence DUX4 expression. Consequently, molecular diagnosis of FSHD is challenging. We used Oxford Nanopore technology to perform whole-genome sequencing of seven unrelated patients with FSHD, their six unaffected parents, and 10 unaffected controls. All seven patients were successfully identified to harbor one to five D4Z4 repeat units and the polyA signal, whereas none of the 16 unaffected individuals met the molecular diagnostic criteria. Our newly developed method provides a straightforward and powerful molecular diagnostic tool for FSHD.

High-Throughput Contractile Measurements of Hydrogel-Embedded Intact Mouse Muscle Fibers Using an Optics-Based System.

In vitro cell culture is a powerful tool to assess cellular processes and test therapeutic strategies. For skeletal muscle, the most common approaches involve either differentiating myogenic progenitor cells into immature myotubes or the short-term ex vivo culture of isolated individual muscle fibers. A key benefit of ex vivo culture over in vitro is the retention of the complex cellular architecture and contractile characteristics. Here, we detail an experimental protocol for the isolation of intact flexor digitorum brevis muscle fibers from mice and their subsequent ex vivo culture. In this protocol, muscle fibers are embedded in a fibrin-based and basement membrane matrix hydrogel to immobilize the fibers and maintain their contractile function. We then describe methods to assess the muscle fiber contractile function using an optics-based, high-throughput contractility system. The embedded muscle fibers are electrically stimulated to induce contractions, after which their functional properties, such as sarcomere shortening and contractile velocity, are assessed using optics-based quantification. Coupling muscle fiber culture with thissystem allows for high-throughput testing of the effects of pharmacological agents on contractile function and ex vivo studies of genetic muscle disorders. Finally, this protocol can also be adapted to study dynamic cellular processes in muscle fibers using live-cell microscopy.

MANOEUVRE Study Design: A Study of GYM329 (RO7204239) in Patients with Facioscapulohumeral Muscular Dystrophy (FSHD) (S2.010)

MANOEUVRE Study Design: A Study of GYM329 (RO7204239) in Patients with Facioscapulohumeral Muscular Dystrophy (FSHD) (S2.010)

Effect of Panchakarma therapy in the management of congenital muscular dystrophy

Congenital Muscular Dystrophy (CMD) is a general term for a group of genetic muscle disorder that occurs at birth (congenital) or early infancy. Muscular dystrophies are characterized by weakness and degeneration of various voluntary muscles of the body. The severity, specific symptoms, and progression of these disorders vary greatly. A six and half-year-old female child was brought by her parents to the outpatient department (OPD) of Kaumarabhritya department, with the chief complaints of toe walking, unable to balance her body, tremors while standing, unable to stand from a sitting position without support, and unable to lift up both legs from the supine position. The patient visited the OPD with a diagnosis as CMD. After examination, internal medications: Bilwadi gutika, Ashwagandha churna, Pippali churna, Pravala bhasma, and Shirisharishta were prescribed along with Panchakarma procedures (~five therapeutic procedures) including Udwartana (~therapeutic massage using powders), Sarvanga abhyanga (~whole body oil massage), Swedana (~sudation therapy), Niruha basti (~therapeutic decoction enema), and Anuvasana basti (~therapeutic unctuous enema). After treatment, improvement in muscle power was seen. The total score of the Barthel index before the study was 70 and after the study was 95, which shows improvement in activity of daily life. Serum creatine phosphokinase and serum creatine kinase-MB values were insignificantly improved before and after treatment. Liver function test, kidney function test, and electrocardiogram before and after treatment were within normal limits, this shows the safety of the internal medication and Ayurvedic Panchakarma procedures. Improvement in the activity of daily life and muscle power seen in the present case gives hope, where there are still no satisfactory management options for patients with CMD are available.

NEB mutations disrupt the super-relaxed state of myosin and remodel the muscle metabolic proteome in nemaline myopathy

Nemaline myopathy (NM) is one of the most common non-dystrophic genetic muscle disorders. NM is often associated with mutations in the NEB gene. Even though the exact NEB-NM pathophysiological mechanisms remain unclear, histological analyses of patients’ muscle biopsies often reveal unexplained accumulation of glycogen and abnormally shaped mitochondria. Hence, the aim of the present study was to define the exact molecular and cellular cascade of events that would lead to potential changes in muscle energetics in NEB-NM. For that, we applied a wide range of biophysical and cell biology assays on skeletal muscle fibres from NM patients as well as untargeted proteomics analyses on isolated myofibres from a muscle-specific nebulin‐deficient mouse model. Unexpectedly, we found that the myosin stabilizing conformational state, known as super-relaxed state, was significantly impaired, inducing an increase in the energy (ATP) consumption of resting muscle fibres from NEB-NM patients when compared with controls or with other forms of genetic/rare, acquired NM. This destabilization of the myosin super-relaxed state had dynamic consequences as we observed a remodeling of the metabolic proteome in muscle fibres from nebulin‐deficient mice. Altogether, our findings explain some of the hitherto obscure hallmarks of NM, including the appearance of abnormal energy proteins and suggest potential beneficial effects of drugs targeting myosin activity/conformations for NEB-NM.

787 A CASE OF LEFT-DOMINANT ARRHYTHMOGENIC CARDIOMYOPATHY

Abstract The case we present involves a 45-years-old male patient who presented to the Emergency Department of our Hospital complaining of epigastric increasing pain associated with nausea and vomiting since the previous afternoon. During night patient had a syncopal episode after having had the feeling of pounding heart at the moment he was having a diarrheal bowel movement. Blood test showed no HS-Troponin nor D-dimer increase. Consultant cardiologist decided to test patient with an exercise test that showed polymorphic ventricular ectopic beats thus leading to hospitalization in our Cardiology Unit. Here patient was asymptomatic and hemodynamically stable during the whole period. He underwent an echocardiography showing no abnormal findings. For this reason, our team decided to perform a Cardiac Magnetic Resonance that showed LGE at subepicardial level in mid-apical segment of inferior wall and apical segment of interventricular septum. What's more, “India ink artifact” as of intramyocardial adipose infiltration was evident. Not having made a final diagnosis we decided to implant a Loop Recorder and asked patient to wear a wearable cardiac defibrillator. Genetic testing was also ordered to search for common mutations involved in Arrhythmogenic cardiomyopathy. At discharge, a therapy with metoprolol 50 mg twice per day was prescribed. Two months later, the result of genetics confirmed the diagnosis of Arrhythmogenic Cardiomyopathy with left ventricular involvement and the patient entered our Unit to undergo Implantable Cardioverter-Defibrillator (ICD) positioning for primary prevention of sudden cardiac death (SCD). Arrhythmogenic Cardiomyopathy (AC) is a genetic heart muscle disorder whose main pathological feature is normal myocardial tissue replacement by fibrofatty scar tissue and clinical presentation with life-threatening ventricular arrhythmias associated or not with global or regional ventricular systolic dysfunction. Although it was firstly described a predominant right ventricle involvement, nowadays it is known the existence of biventricular and even left-dominant phenotype. Prevalence is estimated between 1:1000 and 1:5000. AC occurs all over the world but has an increased prevalence in Northeastern Italy area. Pathologically fibrofatty tissue replacement begins from the subepicardial layers of myocardium towards subendocardial to become transmural. Diagnosis is made following a scoring system firstly created in 1994, then revised in 2010 and again in 2020, when the so-called Padua criteria were proposed. They are divided in 6 different categories: morpho-functional ventricular abnormalities, structural myocardial abnormalities, repolarization and depolarization abnormalities, ventricular arrhythmias, genetics. Demonstration of mutation in left-dominant AC related genes is mandatory for diagnosis because clinical and imaging features are not specific for this condition. Our case demonstrates a challenging diagnosis of left-dominant AC with a perfect example of Padua criteria implementation, because our patient had structural myocardial abnormalities as LGE by CMR plus had a positive molecular genetic testing.

Identification of Auxiliary Biomarkers and Description of the Immune Microenvironmental Characteristics in Duchenne Muscular Dystrophy by Bioinformatical Analysis and Experiment.

BackgroundDuchenne muscular dystrophy (DMD) is a genetic muscle disorder characterized by progressive muscle wasting associated with persistent inflammation. In this study, we aimed to identify auxiliary biomarkers and further characterize the immune microenvironment in DMD.MethodsDifferentially expressed genes (DEGs) were identified between DMD and normal muscle tissues based on Gene Expression Omnibus (GEO) datasets. Bioinformatical analysis was used to screen and identify potential diagnostic signatures of DMD which were further validated by real-time quantitative reverse transcription PCR (RT-qPCR). We also performed single-sample gene-set enrichment analysis (ssGSEA) to characterize the proportion of tissue-infiltrating immune cells to determine the inflammatory state of DMD.ResultsIn total, 182 downregulated genes and 263 upregulated genes were identified in DMD. C3, SPP1, TMSB10, TYROBP were regarded as adjunct biomarkers and successfully validated by RT-qPCR. The infiltration of macrophages, CD4+, and CD8+ T cells was significantly higher (p < 0.05) in DMD compared with normal muscle tissues, while the infiltration of activated B cells, CD56dim natural killer cells, and type 17 T helper (Th17) cells was lower. In addition, the four biomarkers (C3, SPP1, TMSB10, TYROBP) were strongly associated with immune cells and immune-related pathways in DMD muscle tissues.ConclusionAnalyses demonstrated C3, SPP1, TMSB10, and TYROBP may serve as biomarkers and enhance our understanding of immune responses in DMD. The infiltration of immune cells into the muscle microenvironment might exert a critical impact on the development and occurrence of DMD.

Myosin dysregulation in RyR1 related myopathies

Conditions related to mutations in the gene encoding ryanodine receptor 1 (RyR1) are among the most common non-dystrophic genetic muscle disorders, and encompass Malignant Hyperthermia aswell as Central Core Disease. Even though, we now know that these two conditions are highly related to RyR1 malfunction and subsequent calcium transient maladaptation within muscle fibres, the exact mechanisms underlying muscle dysfunction are likely to be more complex and may include a remodeling of other major contractile proteins with molecular and cellular functional consequences.

The Performance of Upper Limb (PUL) module in limb-girdle muscular dystrophy.

Limb-girdle muscular dystrophy (LGMD) is a genetic muscle disorder causing weakness and wasting of the proximal limb musculature. When ambulation is lost, the attention must be shifted to the upper limb muscles' function. We studied the upper limb muscle strength and the corresponding function in 15 LGMDR1/LGMD2A and 13 LGMDR2/LGMD2B, through the Performance of Upper Limb scale and the MRC score of upper limbs. The proximal item K and the distal items N and R were lower in LGMD2B/R2. The mean MRC score of all the muscles involved linearly correlated (r2 = 0.922) for item K in LGMD2B/R2. The functional worsening paralleled the muscles weakness in LGMD2B/R2. By contrast, at proximal level the function of LGMD2A/R1 was preserved despite muscle weakness was present, presumably due to compensatory strategies. Sometimes the combination of parameters might be more informative than considering them separately. PUL scale and MRC might be interesting outcome measures in non-ambulant patients.

Spatio-temporal gait differences in Facioscapulohumeral muscular dystrophy during single and dual task overground walking - A pilot study

Facioscapulohumeral muscular dystrophy (FSHD) is a rare genetic muscle disorder leading to progressive muscle loss over time. Research indicates that this progressive muscular atrophy can negatively impact spatio-temporal gait characteristics, but this is not always the case during early-onset or mild cases of the disease. In addition, the performance of a secondary task during overground walking may elucidate greater deficits in spatio-temporal characteristics of gait. However, such dual task effects on FSHD gait have not been studied thus far. The current study aimed to (a) quantify changes in spatio-temporal gait parameters in individuals with FSHD using the Tekscan Strideway gait mat system, (b) measure the dual task (DT) effects on cadence and gait velocity during single task (ST) and DT overground walking in FSHD and healthy controls and (c) investigate the correlation between the gait parameters and the methylation status in FSHD. Nine FSHD (M±SD=52.78±14.69 years) and nine nearly matched healthy controls (M±SD=50.11±16.18 years) performed five ST and five DT walking in a pseudo-randomized order. The DT included a serial 7's subtraction task from a random number between 50 and 100. Dependent variables: Cadence (steps/min) and gait velocity (cm/sec) were obtained from Tekscan Strideway (30 Hz, Boston, MA). The pairwise comparison indicated that cadence was significantly different for both ST (P<0.004) and DT (P<0.02) where FSHD showed lower cadence compared to controls. Gait velocity was also significantly lower for FSHD during ST (P<0.004) and DT (P<0.008). Multilevel modeling (MLM) approach revealed a group by task interaction for cadence (P<0.05) and gait velocity (P<0.001). The interaction showed a significant difference between ST and DT in controls for cadence and gait velocity. However, there was no difference between ST and DT in FSHD. Finally, a comparison of methylation percentage versus gait parameters revealed a significant negative correlation coefficient for cadence but not for gait velocity. These results indicate specific pairwise differences in both ST and DT walking, observed in the gait parameters as decreased cadence and gait velocity during ST and DT. In addition, the MLM showed that controls exhibited the DT cost as expected but FSHD did not for cadence and gait velocity. ST appears to be sufficiently challenging in FSHD and results in overall declines in spatio-temporal characteristics of gait. Further research is needed to test this paradigm with early-onset or mild cases to track disease progression and its effects on ambulation.

Reticulon-1C Involvement in Muscle Regeneration.

Skeletal muscle is a very dynamic and plastic tissue, being essential for posture, locomotion and respiratory movement. Muscle atrophy or genetic muscle disorders, such as muscular dystrophies, are characterized by myofiber degeneration and replacement with fibrotic tissue. Recent studies suggest that changes in muscle metabolism such as mitochondrial dysfunction and dysregulation of intracellular Ca2+ homeostasis are implicated in many adverse conditions affecting skeletal muscle. Accumulating evidence also suggests that ER stress may play an important part in the pathogenesis of inflammatory myopathies and genetic muscle disorders. Among the different known proteins regulating ER structure and function, we focused on RTN-1C, a member of the reticulon proteins family localized on the ER membrane. We previously demonstrated that RTN-1C expression modulates cytosolic calcium concentration and ER stress pathway. Moreover, we recently reported a role for the reticulon protein in autophagy regulation. In this study, we found that muscle differentiation process positively correlates with RTN-1C expression and UPR pathway up-regulation during myogenesis. To better characterize the role of the reticulon protein alongside myogenic and muscle regenerative processes, we performed in vivo experiments using either a model of muscle injury or a photogenic model for Duchenne muscular dystrophy. The obtained results revealed RTN-1C up-regulation in mice undergoing active regeneration and localization in the injured myofibers. The presented results strongly suggested that RTN-1C, as a protein involved in key aspects of muscle metabolism, may represent a new target to promote muscle regeneration and repair upon injury.

Impact and predictors of quality of life in adults diagnosed with a genetic muscle disorder: a nationwide population-based study.

To determine the impact of genetic muscle disorders and identify the sociodemographic, illness, and symptom factors influencing quality of life. Adults (aged 16-90years) with a confirmed clinical or molecular diagnosis of a genetic muscle disorder identified as part of a nationwide prevalence study were invited to complete an assessment of the impact of their condition. Quality of life was measured using the World Health Organization Quality of Life questionnaire. Impact was measured via the prevalence of symptoms and comparisons of quality of life against New Zealand norms. Multivariate regression models were used to identify the most significant predictors of quality of life domains. 490/596 participants completed the assessment (82.2% consent rate). Quality of life was lower than the general population on physical (t = 9.37 p < 0.0001, d = 0.54) social (t = 2.27 p = 0.02, d = 0.13) and environmental domains (t = 2.28 p = 0.02, d = 0.13), although effect sizes were small. No difference was found on the psychological domain (t = - 1.17 p = 0.24, d = 0.07). Multivariate regression models (predicting 42%-64% of the variance) revealed personal factors (younger age, being in employment and in a relationship), symptoms (lower pain, fatigue, and sleep difficulties), physical health (no need for ventilation support, fewer activity limitations and no comorbidities), and psychosocial factors (lower depression, anxiety, behavioural dyscontrol and higher self-efficacy, satisfaction with health care and social support) contributed to improved quality of life. A range of factors influence the quality of life in adults diagnosed with a genetic muscle disorder and some may serve as targets for multi-faceted intervention.