A Preclinical Model of Sepsis-Induced Myopathy with Disuse in Mice.

Sepsis is a major cause of in-hospital deaths. Improvements in treatment result in a greater number of sepsis survivors. Approximately 75% of the survivors develop muscle weakness and atrophy, increasing the incidence of hospital readmissions and mortality. However, the available preclinical models of sepsis do not address skeletal muscle disuse, a key component for the development of sepsis-induced myopathy. Our objective in this protocol is to provide a step-by-step guideline for a mouse model that reproduces the clinical setting experienced by a bedridden septic patient. Male C57Bl/6 mice were used to develop this model. Mice underwent cecal ligation and puncture (CLP) to induce sepsis. Four days post-CLP, mice were subjected to hindlimb suspension (HLS) for seven days. Results were compared with sham-matched surgeries and/or animals with normal ambulation (NA). Muscles were dissected for in vitro muscle mechanics and morphological assessments. The model results in marked muscle atrophy and weakness, a similar phenotype observed in septic patients. The model represents a platform for testing potential therapeutic strategies for the mitigation of sepsis-induced myopathy.

Screening primary carnitine deficiency in 10 million Chinese newborns: a systematic review and meta-analysis.

BACKGROUND: Primary carnitine deficiency (PCD) is a rare autosomal recessive fatty acid oxidation disorder caused by variants in SLC22A5, with its prevalence and SLC22A5 gene mutation spectrum varying across races and regions. This study aimed to systematically analyze the incidence of PCD in China and delineate regional differences in the prevalence of PCD and SLC22A5 gene variants. METHODS: PubMed, Embase, Web of Science, and Chinese databases were searched up to November 2023. Following quality assessment and data extraction, a meta-analysis was performed on screening results for PCD among Chinese newborns. RESULTS: After reviewing 1,889 articles, 22 studies involving 9,958,380 newborns and 476 PCD cases were included. Of the 476 patients with PCD, 469 underwent genetic diagnosis, revealing 890 variants of 934 alleles of SLC22A5, among which 107 different variants were detected. The meta-analysis showed that the prevalence of PCD in China was 0.05‰ [95%CI, (0.04‰, 0.06‰)] or 1/20 000 [95%CI, (1/16 667, 1/25 000)]. Subgroup analyses revealed a higher incidence in southern China [0.07‰, 95%CI, (0.05‰, 0.08‰)] than in northern China [0.02‰, 95%CI, (0.02‰, 0.03‰)] (P < 0.001). Furthermore, the result of the meta-analysis showed that the frequency of the variant with c.1400C > G, c.51C > G, c.760C > T, c.338G > A, and c.428C > T were 45% [95%CI, (34%, 59%)], 26% [95%CI, (22%, 31%)], 14% [95%CI, (10%, 20%)], 6% [95%CI, (4%, 8%)], and 5% [95%CI, (4%, 8%)], respectively. Among the subgroup analyses, the variant frequency of c.1400C > G in southern China [39%, 95%CI, (29%, 53%)] was significantly lower than that in northern China [79‰, 95%CI, (47‰, 135‰)] (P < 0.05). CONCLUSIONS: This study systematically analyzed PCD prevalence and identified common SLC22A5 gene variants in the Chinese population. The findings provide valuable epidemiological insights and guidance for future PCD screening effects in newborns.

Skeletal muscle involvement in systemic amyloidosis is often overlooked.

AIM: Systemic amyloidosis is a condition in which misfolded amyloid fibrils are deposited within tissues. Amyloid myopathy is a rare manifestation of systemic amyloidosis. However, whether skeletal muscle involvement is underestimated and whether such deposition guarantees clinical and pathological myopathic features remain to be investigated. METHODS: We retrospectively reviewed patients with systemic amyloidosis, in whom skeletal muscle biopsies were performed at our centre between January 2018 and June 2023. In total, 28 patients with suspected systemic amyloidosis were included. Among these, 21 presented with cardiomyopathy but lacked myopathic symptoms. The clinical and pathological data of these patients were further analysed. The amyloid type was confirmed by immunohistochemistry. RESULTS: Twenty-eight patients with suspected systemic amyloidosis underwent muscle biopsy. Amyloid deposition in the skeletal muscle was confirmed in 24 patients, including 22 with light-chain amyloidosis (AL) and two with transthyretin amyloidosis (ATTR). Among the 24 patients, seven presented with muscle weakness and decreased muscle strength (Group 1, symptomatic myopathy), whereas the remaining 17 exhibited normal muscle strength (Group 2, asymptomatic myopathy). Group 1 included four patients with AL-λ, one with AL-κ and two with ATTR. Group 2 included 15 patients with AL-λ and two patients with AL-κ. In Group 1, six patients exhibited neuropathy, whereas only one patient in Group 2 presented with subclinical neuropathy on nerve conduction studies. Amyloid deposition in the interstitium was the most obvious change, observed in all 24 patients. Neuropathic changes, including denervation atrophy and muscle fibre grouping, were also common. Except for type 2 fibre atrophy, the other myopathic changes were mild and nonspecific. No sarcolemmal disruption was observed. Immunohistochemical analysis revealed marked positivity for MAC and MHC1 expression in the regions with amyloid deposits. Clinicopathological analysis revealed no significant differences in the extent of muscular amyloid deposition between the two groups. Nevertheless, patients in Group 1 displayed more pronounced neurogenic atrophy on skeletal muscle biopsies. CONCLUSIONS: Our study indicates that amyloid deposition in skeletal muscle is commonly observed but rarely causes symptomatic myopathy in systemic amyloidosis.

Development of a local controlled release system for therapeutic proteins in the treatment of skeletal muscle injuries and diseases.

The present study aims to develop and characterize a controlled-release delivery system for protein therapeutics in skeletal muscle regeneration following an acute injury. The therapeutic protein, a membrane-GPI anchored protein called Cripto, was immobilized in an injectable hydrogel delivery vehicle for local administration and sustained release. The hydrogel was made of poly(ethylene glycol)-fibrinogen (PEG-Fibrinogen, PF), in the form of injectable microspheres. The PF microspheres exhibited a spherical morphology with an average diameter of approximately 100 micrometers, and the Cripto protein was uniformly entrapped within them. The release rate of Cripto from the PF microspheres was controlled by tuning the crosslinking density of the hydrogel, which was varied by changing the concentration of poly(ethylene glycol) diacrylate (PEG-DA) crosslinker. In vitro experiments confirmed a sustained-release profile of Cripto from the PF microspheres for up to 27 days. The released Cripto was biologically active and promoted the in vitro proliferation of mouse myoblasts. The therapeutic effect of PF-mediated delivery of Cripto in vivo was tested in a cardiotoxin (CTX)-induced muscle injury model in mice. The Cripto caused an increase in the in vivo expression of the myogenic markers Pax7, the differentiation makers eMHC and Desmin, higher numbers of centro-nucleated myofibers and greater areas of regenerated muscle tissue. Collectively, these results establish the PF microspheres as a potential delivery system for the localized, sustained release of therapeutic proteins toward the accelerated repair of damaged muscle tissue following acute injuries.

Exome sequencing in undiagnosed congenital myopathy reveals new genes and refines genes-phenotypes correlations.

BACKGROUND: Congenital myopathies are severe genetic diseases with a strong impact on patient autonomy and often on survival. A large number of patients do not have a genetic diagnosis, precluding genetic counseling and appropriate clinical management. Our objective was to find novel pathogenic variants and genes associated with congenital myopathies and to decrease diagnostic odysseys and dead-end. METHODS: To identify pathogenic variants and genes implicated in congenital myopathies, we established and conducted the MYOCAPTURE project from 2009 to 2018 to perform exome sequencing in a large cohort of 310 families partially excluded for the main known genes. RESULTS: Pathogenic variants were identified in 156 families (50%), among which 123 families (40%) had a conclusive diagnosis. Only 44 (36%) of the resolved cases were linked to a known myopathy gene with the corresponding phenotype, while 55 (44%) were linked to pathogenic variants in a known myopathy gene with atypical signs, highlighting that most genetic diagnosis could not be anticipated based on clinical-histological assessments in this cohort. An important phenotypic and genetic heterogeneity was observed for the different genes and for the different congenital myopathy subtypes, respectively. In addition, we identified 14 new myopathy genes not previously associated with muscle diseases (20% of all diagnosed cases) that we previously reported in the literature, revealing novel pathomechanisms and potential therapeutic targets. CONCLUSIONS: Overall, this approach illustrates the importance of massive parallel gene sequencing as a comprehensive tool for establishing a molecular diagnosis for families with congenital myopathies. It also emphasizes the contribution of clinical data, histological findings on muscle biopsies, and the availability of DNA samples from additional family members to the diagnostic success rate. This study facilitated and accelerated the genetic diagnosis of congenital myopathies, improved health care for several patients, and opened novel perspectives for either repurposing of existing molecules or the development of novel treatments.

[Clinical characteristics and genetic analysis of a child with Neutral lipid storage disease with myopathy].

OBJECTIVE: To explore the clinical phenotype and genetic basis of a child with Neutral lipid storage disease with myopathy (NLSDM). METHODS: A child who was admitted to the First Affiliated Hospital of Zhengzhou University in February 2021 for a history of elevated creatine kinase (CK) for over 2 months was selected as the study subject. Clinical and laboratory examinations were carried out, and the child was subjected to whole exome sequencing. Candidate variants were validated by Sanger sequencing of her family members. RESULTS: The patient, a 9-year-old female, had exhibited weakness in the lower limbs, elevated CK level, and refractory cardiomyotrophy. Genetic testing revealed that she has harbored c.32C>G (p.S11W) and c.516C>G (p.N172K) compound heterozygous variants of the PNPLA2 gene, which were respectively inherited from her mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PM1+PM2_Supporting+PP3+PP4). CONCLUSION: The c.32C>G (p.S11W) and c.516C>G (p.N172K) compound heterozygous variants of the PNPLA2 gene probably underlay the myasthenia gravis and elevated creatine kinase in this child.

Myotendinopathy of Unknown Etiology in Broiler Breeder Males.

This case series describes an emerging and ongoing lameness condition observed in broiler breeder males in flocks owned by a broiler integrator in the United States between February 2021 and April 2023. The lameness is characterized by an upright, penguin-like posture and gait. Affected flocks are typically 12-22 wk of age at presentation, but birds with similar stance and gross lesions can be observed as early as 1 day of age. Male mortality associated with this condition ranges from 0.01% to 6% per flock. The condition is infrequently observed in pullets from the female line but has not been observed in males (sex slips) from the female line. On postmortem examination, affected birds have bilateral hemorrhage due to a tearing of the iliotibialis muscles and fascia. In one case, a higher proportion of affected birds had unilateral lesions concurrently with broken legs or severe inguinal vaccine reaction. In this case, the affected leg was the weight-bearing leg. Histopathology confirmed the presence of hemorrhage in fascial sheaths surrounding major muscles, in addition to muscle fiber necrosis, edema, fibroplasia, and dissociation of tendon collagen. Bacteriology, histopathology, and clinical presentation identified no factors that were suggestive of an infectious etiology for this condition. No etiology has been established, but a suggested pathogenesis involves excessive biomechanical force resulting in tendon structural stress, leading to separation of tendon collagen fibers and associated muscle fiber stretching, separation, necrosis, and hemorrhage. The condition has been reported in multiple genetic lines, but the role of inheritance in the condition has not been fully evaluated.

Miotendinopatía de etiología desconocida en machos reproductores pesados. Esta serie de casos describe una condición de cojera emergente y recurrente observada en parvadas de machos reproductores pesados propiedad de un integrador de pollo de engorde en los Estados Unidos entre febrero del 2021 y abril del 2023. La cojera se caracteriza por una postura y desplazamientos corporales en forma erguida, parecidos a los de los pingüinos. Las parvadas afectadas suelen tener entre 12 y 22 semanas de edad en el momento de la presentación, pero se han podido observar aves con similar postura corporal y lesiones macroscópicas tan temprano como al primer día de edad. La mortalidad de los machos asociada con esta condición oscila entre el 0.01% y el 6% por parvada. La condición se observa con poca frecuencia en pollitas de la línea hembra, pero no se ha observado en machos provenientes de la misma línea hembra (errores de sexado). En el examen post mortem, las aves afectadas presentan hemorragia bilateral debido a un desgarramiento de los músculos iliotibiales y la fascia. En un caso, una mayor proporción de aves afectadas tuvieron lesiones unilaterales simultáneamente con patas rotas o una reacción postvacunal severa en la región inguinal. En este caso, la pierna afectada era la misma que soportaba peso. La histopatología confirmó la presencia de hemorragia en las vainas fasciales que rodean los músculos principales, además de necrosis de fibras musculares, edema, fibroplasia y disociación del colágeno del tendón. Mediante la bacteriología, la histopatología y la presentación clínica no se identificaron factores que sugirieran una etiología infecciosa para esta afección. No se ha establecido una etiología, pero una patogénesis sugerida implica una fuerza biomecánica excesiva que produce estrés estructural del tendón, lo que lleva a la separación de las fibras de colágeno del tendón y al estiramiento, separación, necrosis y hemorragia de las fibras musculares asociadas. La afección se ha informado en múltiples líneas genéticas, pero no se ha evaluado completamente el papel de la genética en esta condición.

Myonecrosis as a rare side effect of stereotactic body radiotherapy for bone metastases: Report of two cases and a comprehensive literature review.

Stereotactic body radiotherapy is a highly effective form of radiation therapy for palliation of bone metastases, but it can also lead to rare but severe side effects, such as myonecrosis. According to the literature, the incidence of myonecrosis after stereotactic body radiotherapy is low and mostly dose dependent. It is crucial to consider the potential impact of immunotherapy and other systemic therapies in the assessment. The course of radiation myonecrosis can vary, and corticosteroids or vascular endothelial growth factor inhibitors may potentially play a role in its treatment. Herein, we report two patients presenting with myonecrosis after stereotactic body radiotherapy for bone metastasis.

Combined regenerative rehabilitation improves recovery following volumetric muscle loss injury in a rat model.

Volumetric muscle loss (VML) injury causes irreversible deficits in muscle mass and function, often resulting in permanent disability. The current standard of care is physical therapy, but it is limited in mitigating functional deficits. We have previously optimized a rehabilitation technique using electrically stimulated eccentric contraction training (EST) that improved muscle mass, strength, and size in VML-injured rats. A biosponge scaffold composed of extracellular matrix proteins has previously enhanced muscle function postVML. This study aimed to determine whether combining a regenerative therapy (i.e., biosponge) with a novel rehabilitation technique (i.e., EST) could enhance recovery in a rat model of VML. A VML defect was created by removing ~20% of muscle mass from the tibialis anterior muscle in adult male Lewis rats. Experimental groups included VML-injured rats treated with biosponge with EST or biosponge alone (n = 6/group). EST was implemented 2 weeks postinjury at 150 Hz and was continued for 4 weeks. A linear increase in eccentric torque over 4 weeks showed the adaptability of the VML-injured muscle to EST. Combining biosponge with EST improved peak isometric torque by ~52% compared with biosponge treatment alone at 6 weeks postinjury. Application of EST increased MyoD gene expression and the percentage of large (>2000 µm2) type 2B myofibers but reduced fibrotic tissue deposition in VML-injured muscles. Together, these changes may provide the basis for improved torque production. This study demonstrates the potential for combined regenerative and rehabilitative therapy to improve muscle recovery following VML.

The Multifaceted Cause of Lipid Storage Myopathies, Genetics, and Treatment.

Several inherited metabolic fatty acid disorders present with myopathies. Skeletal muscle accounts for 40% of the body and is important for metabolism, exercise, and movement. Muscle energy failure is manifested by metabolic crises with muscle weakness, sometimes associated with muscle fatigue and failure resulting in acute necrosis or rhabdomyolysis/myoglobinuria episodes. Lack of energy leads to muscle necrosis. Other presentations are weakness and myalgias with lipid storage myopathies in the biopsy. The biomarkers of such disorders are acyl-carnitine with various profiles and need to be carefully evaluated to plan supplementary therapy and specific diets. If red flags are not distinctly followed and diagnosed in time they might lead to a metabolic or cardiac failure.

Compound Muscle Action Potential and Myosin-Loss Pathology in Patients With Critical Illness Myopathy: Correlation and Prognostication.

BACKGROUND AND OBJECTIVES: Prolonged compound muscle action potential (CMAP) duration and preferential loss of myosin are considered the diagnostic hallmarks of critical illness myopathy (CIM); however, their correlation and prognostic values have not been studied. We aimed to investigate the correlation between CMAP duration and myosin loss and their effect on mortality by comparing between patients with CIM with and without myosin loss. METHODS: We searched the Mayo Clinic Electromyography Laboratory databases (1986-2021) for patients diagnosed with CIM on the basis of prolonged distal CMAP durations (>15 msec in fibular motor nerve studies recording over the tibialis anterior or >8 msec in other motor nerves) and needle EMG findings compatible with myopathy. Electrodiagnostic studies were generally performed within 24 hours after weakness became noticeable. We included only patients who underwent muscle biopsy. Clinical, electrophysiologic, and myopathologic data were reviewed. We conducted myosin/actin ratio analysis when muscle tissue was available. We used the Fisher exact test for categorical data comparisons and the Mann-Whitney 2-tailed test for continuous data. We applied the Kaplan-Meier technique to analyze survival rates. RESULTS: Twenty patients (13 female patients) were identified [median age at diagnosis of 62.5 years (range: 19-80 years)]. The median onset of weakness was 24 days (range: 1-128) from the first day of intensive care unit admission. Muscle biopsy showed myosin loss in 14 patients, 9 of whom had >50% of myofibers affected (high grade). Type 2 fiber atrophy was observed in 19 patients, 13 of whom also had myosin loss. Patients with myosin loss had higher frequency of steroid exposure (14 vs 3; p = 0.004); higher median number of necrotic fibers per low-power field (2.5 vs 1, p = 0.04); and longer median CMAP duration (msec) of fibular (13.4 vs 8.75, p = 0.02), tibial (10 vs 7.8, p = 0.01), and ulnar (11.1 vs 7.95, p = 0.002) nerves compared with those without. Only patients with high-grade myosin loss had reduced myosin/actin ratios (<1.7). Ten patients died during median follow-up of 3 months. The mortality rate was similar between patients with and without myosin loss. Patients with high-grade myosin loss had a lower overall survival rate than those with low-grade or no myosin loss, but this was not statistically significant (p = 0.05). DISCUSSION: Myosin loss occurred in 70% of the patients with CIM with prolonged CMAP duration. Longer CMAP duration predicts myosin-loss pathology. The extent of myosin loss marginally correlates with the mortality rate. Our findings highlight the potential prognostic values of CMAP duration and myosin loss severity in predicting disease outcome.

Unlocking the Nexus of Sirtuins: A Comprehensive Review of Their Role in Skeletal Muscle Metabolism, Development, and Disorders.

The sirtuins constitute a group of histone deacetylases reliant on NAD+ for their activity that have gained recognition for their critical roles as regulators of numerous biological processes. These enzymes have various functions in skeletal muscle biology, including development, metabolism, and the body's response to disease. This comprehensive review seeks to clarify sirtuins' complex role in skeletal muscle metabolism, including glucose uptake, fatty acid oxidation, mitochondrial dynamics, autophagy regulation, and exercise adaptations. It also examines their critical roles in developing skeletal muscle, including myogenesis, the determination of muscle fiber type, regeneration, and hypertrophic responses. Moreover, it sheds light on the therapeutic potential of sirtuins by examining their impact on a range of skeletal muscle disorders. By integrating findings from various studies, this review outlines the context of sirtuin-mediated regulation in skeletal muscle, highlighting their importance and possible consequences for health and disease.

Anasarca and spontaneous intramuscular haemmorhage in a dermatomyositis patient: case report and review of the literature.

Dermatomyositis is a rare, autoimmune systemic disorder of unknown aetiology that presents as a constellation of clinical symptoms and signs primarily affecting skin and muscles. Patients with dermatomyositis can present with rare "non-canonical" manifestations. Focal or generalised oedema is an infrequent and often overlooked symptom of the disease, while spontaneous intramuscular haemorrhage is an even rarer and under-recognised, life-threatening complication that constitutes a medical emergency for clinical physicians. There are no known predisposing factors able to predict which patients will develop this complication and specific instructions considering treatment approach are currently lacking. Herein, we present a case of a patient with dermatomyositis complicated by both anasarca and spontaneous intramuscular haemorrhage. In order to raise awareness and timely diagnosis of such patients, we provide a review of the relevant literature and of the cases reported this far.

Miopatías RYR1 en la infancia: correlación fenotipo-genotipo e incidencia / RYR1 myopathies in childhood: phenotype-genotype correlation and incidence

Introducción: Las miopatías relacionadas con el receptor de rianodina de tipo 1 (RYR1-RM) constituyen la categoría más frecuente de miopatías congénitas. La introducción de técnicas genéticas ha cambiado el paradigma diagnóstico y sugiere la prioridad de estudios moleculares sobre biopsias. Este estudio busca explorar las características clinicoepidemiológicas de pacientes con variantes del gen RYR1 en un hospital pediátrico de tercer nivel con el objetivo de ampliar la comprensión de la correlación genotipo-fenotipo en las RYR1-RM. Pacientes y métodos: Estudio observacional, descriptivo y transversal, de pacientes menores de 14 años con síntomas miopáticos y variantes potencialmente patógenas del gen RYR1 entre enero de 2013 y diciembre de 2023, considerando variables como sexo, edad, desarrollo motor, variantes genéticas, patrón de herencia y otras manifestaciones. Todas las variables fueron tabuladas frente a la variante genética. Resultados: De los nueve pacientes incluidos, la incidencia estimada fue de aproximadamente 1/10.000 nacidos vivos. La mediana en el momento del diagnóstico fue de 6 años, con una variabilidad fenotípica significativa. Se observaron síntomas comunes, como debilidad y retraso del desarrollo motor. Las variantes genéticas afectaron al gen RYR1 de manera diversa, y hubo cinco variantes previamente no descritas. La biopsia muscular se realizó en cinco pacientes, en dos de ellos de tipo miopatía central core; en uno, multiminicore; en uno, desproporción congénita de fibras; y en otro, de patrón inespecífico. Conclusiones: Las RYR1-MR de nuestra serie ofrecieron variabilidad fenotípica y de afectación, con una incidencia en nuestra área de en torno a 1/10.000 recién nacidos. La mayoría de los casos fueron varones, de variantes missense dominantes. Aportamos cinco variantes genéticas no descritas con anterioridad.(AU)

Introduction: Ryanodine receptor type 1-related myopathies (RYR1-RM) represent the most prevalent category of congenital myopathies. The introduction of genetic techniques has shifted the diagnostic paradigm, suggesting the prioritization of molecular studies over biopsies. This study aims to explore the clinical and epidemiological characteristics of patients with RYR1 gene variants in a tertiary pediatric hospital, intending to enhance the understanding of the genotype-phenotype correlation in RYR1-RM. Patients and methods: An observational, descriptive, and cross-sectional study was conducted on patients under 14 years old with myopathic symptoms and potentially pathogenic RYR1 gene variants from January 2013 to December 2023. Variables such as gender, age, motor development, genetic variants, inheritance pattern, and other manifestations were considered. All variables were tabulated against the genetic variant. Results: Of the nine included patients, the estimated incidence was approximately 1 in 10,000 live births. The median age at diagnosis was six years, with significant phenotypic variability. Common symptoms such as weakness and delayed motor development were observed. Genetic variants affected the RYR1 gene diversely, including five previously undescribed variants. Muscle biopsy was performed in five patients, revealing central core myopathy in two, multiminicore in one, congenital fiber-type disproportion in one, and a nonspecific pattern in another.(AU)

Successful treatment with reduced oral steroid dosage in an 81-year-old woman with statin-induced anti-HMGCR immune-mediated necrotizing myopathy.

An 81-year-old woman presented with statin-induced anti-HMGCR immune-mediated necrotizing myopathy. Treatment was successful without complications with a reduced oral steroid dosage from the current consensus for all ages and backgrounds. This case suggests the importance of early diagnosis and the possibility of steroid dosage adjustment considering the patient's age, disease severity, and comorbidities.

Proteomic profiling of polyglucosan bodies associated with glycogenin-1 deficiency in skeletal muscle.

AIMS: Polyglucosan storage disorders represent an emerging field within neurodegenerative and neuromuscular conditions, including Lafora disease (EPM2A, EPM2B), adult polyglucosan body disease (APBD, GBE1), polyglucosan body myopathies associated with RBCK1 deficiency (PGBM1, RBCK1) or glycogenin-1 deficiency (PGBM2, GYG1). While the storage material primarily comprises glycans, this study aimed to gain deeper insights into the protein components by proteomic profiling of the storage material in glycogenin-1 deficiency. METHODS: We employed molecular genetic analyses, quantitative mass spectrometry of laser micro-dissected polyglucosan bodies and muscle homogenate, immunohistochemistry and western blot analyses in muscle tissue from a 45-year-old patient with proximal muscle weakness from late teenage years due to polyglucosan storage myopathy. RESULTS: The muscle tissue exhibited a complete absence of glycogenin-1 due to a novel homozygous deep intronic variant in GYG1 (c.7+992T>G), introducing a pseudo-exon causing frameshift and a premature stop codon. Accumulated proteins in the polyglucosan bodies constituted components of glycogen metabolism, protein quality control pathways and desmin. Muscle fibres containing polyglucosan bodies frequently exhibited depletion of normal glycogen. CONCLUSIONS: The absence of glycogenin-1, a protein important for glycogen synthesis initiation, causes storage of polyglucosan that displays accumulation of several proteins, including those essential for glycogen synthesis, sequestosome 1/p62 and desmin, mirroring findings in RBCK1 deficiency. These results suggest shared pathogenic pathways across different diseases exhibiting polyglucosan storage. Such insights have implications for therapy in these rare yet devastating and presently untreatable disorders.

Identification and validation of oxidative stress-related genes in sepsis-induced myopathy.

BACKGROUND: Sepsis-induced myopathy (SIM) a complication of sepsis that results in prolonged mechanical ventilation, long-term functional disability, and increased patient mortality. This study was performed to identify potential key oxidative stress-related genes (OS-genes) as biomarkers for the diagnosis of SIM using bioinformatics. METHODS: The GSE13205 was obtained from the Gene Expression Omnibus (GEO) database, including 13 SIM samples and 8 healthy samples, and the differentially expressed genes (DEGs) were identified by limma package in R language. Simultaneously, we searched for the genes related to oxidative stress in the Gene Ontology (GO) database. The intersection of the genes selected from the GO database and the genes from the GSE13205 was considered as OS-genes of SIM, where the differential genes were regarded as OS-DEGs. OS-DEGs were analyzed using GO enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and protein-protein interaction (PPI) networks. Hub genes in OS-DEGs were selected based on degree, and diagnostic genes were further screened by gene expression and receiver operating characteristic (ROC) curve. Finally, a miRNA-gene network of diagnostic genes was constructed. RESULTS: A total of 1089 DEGs were screened from the GSE13205, and 453 OS-genes were identified from the GO database. The overlapping DEGs and OS-genes constituted 25 OS-DEGs, including 15 significantly upregulated and 10 significantly downregulated genes. The top 10 hub genes, including CD36, GPX3, NQO1, GSR, TP53, IDH1, BCL2, HMOX1, JAK2, and FOXO1, were screened. Furthermore, 5 diagnostic genes were identified: CD36, GPX3, NQO1, GSR, and TP53. The ROC analysis showed that the respective area under the curves (AUCs) of CD36, GPX3, NQO1, GSR, and TP53 were 0.990, 0.981, 0.971, 0.971, and 0.971, which meant these genes had very high diagnostic values of SIM. Finally, based on these 5 diagnostic genes, we found that miR-124-3p and miR-16-5p may be potential targets for the treatment of SIM. CONCLUSIONS: The results of this study suggest that OS-genes might play an important role in SIM. CD36, GPX3, NQO1, GSR, and TP53 have potential as specific biomarkers for the diagnosis of SIM.