BACKGROUND Gastrointestinal(GI)manifestations are prevalent in genetic myopathies,posing significant diagnostic and management challenges.AIM To synthesize evidence on the diagnostic approaches,management strategies,p...BACKGROUND Gastrointestinal(GI)manifestations are prevalent in genetic myopathies,posing significant diagnostic and management challenges.AIM To synthesize evidence on the diagnostic approaches,management strategies,patient perspectives,and future research directions regarding GI symptoms in genetic myopathies.METHODS A systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines.We searched PubMed,Scopus,EMBASE,and Web of Science from inception to December 2024.Eligible studies reported GI manifestations in genetic myopathies,including clinical evaluations,imaging,physiological tests,histopathology,and genetic analyses.Inclusion criteria encompassed original research studies,review articles,case reports,and clinical guidelines published in peer-reviewed journals.Exclusion criteria included conference abstracts without full-text availability and non-peer-reviewed sources.Two independent reviewers screened studies and extracted data.They assessed methodological quality using the Newcastle-Ottawa Scale for observational studies,A MeaSurement Tool to Assess Systematic Reviews for systematic reviews,and the Joanna Briggs Institute checklist for case reports.A systematic narrative synthesis was employed to summarize the findings.RESULTS A total of 234 studies met the inclusion criteria.GI manifestations varied widely,with dysphagia,gastroesophageal reflux,abdominal pain,constipation,diarrhea,and fecal incontinence being the most frequently reported symptoms.The included studies highlighted a multidisciplinary diagnostic approach incorporating clinical assessment,imaging,physiological testing,histopathology,and genetic testing.Management strategies ranged from dietary interventions and rehabilitative therapies to pharmacological treatments and surgical procedures.Patient perspectives underscored the significant impact of GI symptoms on quality of life,social interactions,and emotional well-being.The main limitations of the included studies were high heterogeneity in study design,small sample sizes,and the potential risk of bias due to limited methodological rigor in some reports.CONCLUSION This review underscores the complexity of GI manifestations in genetic myopathies and the need for a comprehensive,multidisciplinary management approach.Future research should focus on elucidating molecular mechanisms,identifying biomarkers,and developing targeted therapies to improve patient outcomes.The findings have implications for both clinical practice and public health,emphasizing the necessity of early diagnosis and personalized management strategies.展开更多
Objective: To assess general pain and fatigue and their association with the disease status of patients with systemic autoimmune myopathies (SAMs), in terms of the impact of the COVID-19 pandemic on these parameters. ...Objective: To assess general pain and fatigue and their association with the disease status of patients with systemic autoimmune myopathies (SAMs), in terms of the impact of the COVID-19 pandemic on these parameters. Methods: This is a cross-sectional and prospective cohort study that included 72 patients with SAMs who were matched by age and gender with 67 healthy individuals. The patients engaged in an interview via a validity survey to measure disease status, and assess a visual analog scale (VAS) for pain and fatigue in two periods: before (phase I) and during (phase II) of the Brazilian COVID-19 pandemic. For cross-sectional analysis, patients’ data from phase I were compared to healthy individuals’ information, whereas for prospective analysis, data of the patients who were assessed in phase II were compared to the same patients’ data from phase I. Results: The patients had significantly more pain perception, comparable fatigue perception and fatigue severity, when compared to the healthy individuals. During the COVID-19 pandemic period, the disease activity, pain and fatigue perceptions, and fatigue severity remained unchanged. Despite this, the pain and fatigue perceptions correlated significantly with patients’ VAS, the patient health outcome, and fatigue severity. In addition, the pain perception correlated to creatine phosphokinase, whereas fatigue perceptions correlated to physicians' VAS. Conclusions: The study showed that patients with SAMs have significantly increased pain perceptions compared to healthy individuals. During the COVID-19 pandemic period, the pain and fatigue perceptions remained unchanged in patients with SAMs but they correlated to several disease status parameters.展开更多
Background： Collagen Vl-related myopathies are autosomal dominant and recessive hereditary myopathies, mainly including Ullrich congenital muscular dystrophy （UCMD） and Bethlem myopathy （BM）. Muscle magnetic reso...Background： Collagen Vl-related myopathies are autosomal dominant and recessive hereditary myopathies, mainly including Ullrich congenital muscular dystrophy （UCMD） and Bethlem myopathy （BM）. Muscle magnetic resonance imaging （MRI） has been widely used to diagnosis muscular disorders. The purpose of this study was to evaluate the diagnostic value of thigh muscles MRI for collagen VI-related myopathies. Methods： Eleven patients with collagen VI gene mutation-related myopathies were enrolled in this study. MRI of the thigh muscles was performed in all patients with collagen VI gene mutation-related myopathies and in 361 patients with other neuromuscular disorders （disease controls）. Tl-weighted images were used to assess fatty infiltration of the muscles using a modified Mercuri＇s scale. We assessed the sensitivity and specificity of the MRI features of collagen Vl-related myopathies. The relationship between fatty infiltration of muscles and specific collagen VI gene mutations was also investigated. Results： Eleven patients with collagen VI gene mutation-related rnyopathies included six UCMD patients and five BM patients. There was no significant difference between UCMD and BM patients in the fatty infiltration of each thigh muscle except sartorius （P = 0.033）： theretbre, we combined the UCMD and BM data. Mean fatty infiltration scores were 3.1 and 3.0 in adductor magnus and gluteus maximus, while the scores were 1.3, 1.3, and 1.5 in gracilis, adductor longus, and sartorius, respectively. A “target” sign in rectus femoris （RF） was present in seven cases, and a “sandwich” sign in vastus lateralis （VL） was present in ten cases. The “target” and “sandwich” signs had sensitivities of 63.6% and 90.9% and specificities of 97.3% and 96,9% for the diagnosis of collagen Vl-related myopathies, respectively. Fatty infiltration scores were 2.0-3.0 in seven patients with mutations in the triple-helical domain, and 1.0-1.5 in three of four patients with mutations in the N- or C-domain of the collagen VI genes. Conclusions： The “target” sign in RF and “sandwich” sign in VL are common MRI features and are useful for the diagnosis of collagen VI-related myopathies. The severity of fatty infiltration of muscles may have a relationship with the mutation location of collagen VI gene.展开更多
Background:Elucidating mechanisms underlying atrial myopathy,which predisposes individuals to atrial fibrillation(AF),will be critical for preventing/treating AF.In a serendipitous discovery,we identified atrial enlar...Background:Elucidating mechanisms underlying atrial myopathy,which predisposes individuals to atrial fibrillation(AF),will be critical for preventing/treating AF.In a serendipitous discovery,we identified atrial enlargement,fibrosis,and thrombi in mice with reduced phosphoinositide 3-kinase(PI3K)in cardiomyocytes.PI3K(p110a)is elevated in the heart with exercise and is critical for exercise-induced ventricular enlargement and protection,but the role in the atria was unknown.Physical inactivity and extreme endurance exercise can increase AF risk.Therefore,our objective was to investigate whether too little and/or too much PI3K alone induces cardiac pathology.Methods:New cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110a)activity were generated.Multi-omics was conducted in mouse atrial tissue,and lipidomics in human plasma.Results:Elevated PI3K led to an increase in heart size with preserved/enhanced function.Reduced PI3K led to atrial dysfunction,fibrosis,arrhythmia,increased susceptibility to atrial enlargement and thrombi,and dysregulation of monosialodihexosylganglioside(GM3),a lipid that regulates insulin-like growth factor-1(IGF1)-PI3K signaling.Proteomic profiling identified distinct signatures and signaling networks acrossatria with varying degrees of dysfunction,enlargement,and thrombi,including commonalities with the human AF proteome.PI3K-related lipids were dysregulated in plasma from athletes with AF.Conclusion:PI3K(p110a)is a critical regulator of atrial biology and function in mice.This work provides a proteomic resource of candidates for further validation as potential new drug targets and biomarkers for atrial myopathy.Further investigation of PI3K-related lipids as markers for identifying individuals at risk of AF is warranted.Dysregulation of PI3K may contribute to the association between increased cardiac risk with physical inactivity and extreme endurance exercise.展开更多
BACKGROUND Mitochondrial myopathies are characterized by primary dysfunction of the mitochondrial respiratory chain;they typically present as chronic muscle weak-ness.Clinically visible acute respiratory dysfunctions ...BACKGROUND Mitochondrial myopathies are characterized by primary dysfunction of the mitochondrial respiratory chain;they typically present as chronic muscle weak-ness.Clinically visible acute respiratory dysfunctions associated with mito-chondrial myopathies occur rarely.CASE SUMMARY In this report,we present the case of a patient who developed postoperative hypoventilation after undergoing an uneventful administration of general anesthesia.A 34-year-old woman with no family history of myopathy underwent laparoscopic removal of a right-sided ureteric stone.Two days postoperatively,her oxygen saturation decreased rapidly,and blood gas analysis revealed hypercapnia.We promptly intubated and initiated the patient and initiated her on mechanical ventilation as she remained awake.Clinical examination findings were unremarkable;the results of laboratory investigations,including those for thyroid,hepatic,renal,and neuromuscular functions,were within normal limits.Muscle biopsy revealed muscle fibers of varying sizes as well as several dege-nerating and regenerating myofibers.Modified Gomori trichrome staining of the cross-sections revealed ragged red fibers.Based on these findings,we diagnosed the patient with mitochondrial myopathy.The patient’s condition gradually improved,and she was discharged on a home ventilator 73 days postoperatively.CONCLUSION Our case highlights that mitochondrial myopathy should be considered in the differential diagnosis of patients with postoperative respiratory failure.展开更多
Dexamethasone is a common glucocorticoid medication with adverse effects that can cause muscle atrophy,but no drug intervention has been approved or recommended for this condition.KF-8 is a rice bran-derived anti-oxid...Dexamethasone is a common glucocorticoid medication with adverse effects that can cause muscle atrophy,but no drug intervention has been approved or recommended for this condition.KF-8 is a rice bran-derived anti-oxidant peptide that extends the lifespan of Caenorhabditis elegans.We established a C.elegans model of dexamethasone-induced myopathy to evaluate the potential therapeutic effects of KF-8 in this model.C.elegans muscle function was assessed in terms of locomotory behaviors including crawling,swimming,burrowing,pharyngeal pumping,and head swing.Muscle actin filament integrity was evaluated using fluorescence imaging.The molecular mechanisms of KF-8 were investigated using transcriptome sequencing,quantitative real-time PCR(qRT-PCR),RNA interference,and Western blot analysis.Dexamethasone disrupted actin filaments in the striated muscles of the body wall and inhibited C.elegans crawling,swimming,burrowing,pharyngeal pumping,and head swing.KF-8 reversed the actin filament disruption and locomotor dysfunction induced by dexamethasone.Transcriptome sequencing,pathway enrichment,and qRT-PCR analyses revealed that KF-8 regulated the locomotion-related genes W04G5.10,vha-12,and ddr-1,as well as age-1(the catalytic subunit ortholog of phosphatidylinositol 3-kinase(PI3K)),and akt1.RNA interference,conducted using a genetically engineered Escherichia coli HT115 strain as a food source,confirmed age-1 as a key regulator of locomotor function of C.elegans.Further mechanistic studies with C2C12 myotubes showed that KF-8 regulated the IRS-PI3K-Akt pathway,the master regulator of protein synthesis and degradation.Together,these findings suggest that KF-8 protects against dexamethasoneinduced myopathy in C.elegans by regulating locomotion-related genes and the IRS-PI3K-Akt pathway.展开更多
Background:Most mutations in the COL6A3 gene lead to collagen VI-related myopathies.This is due to a reduced expression or mislocalization of the COL6A3 protein.Therefore,studying the consequence of knocking out the C...Background:Most mutations in the COL6A3 gene lead to collagen VI-related myopathies.This is due to a reduced expression or mislocalization of the COL6A3 protein.Therefore,studying the consequence of knocking out the Col6a3 gene in mouse models is relevant,but the Col6a3 mouse models reported so far do not entirely abolish COL6A3 protein expression.Methods:Here,we present the development,validation and preliminary phenotypic characterization of a novel CRISPR-based knockout mouse model targeting Col6a3 exon 3(Col6a3^(d3/d3)).Results:In this mouse model,Col6a3 mRNA is still expressed at a similar level to wild-type littermates,although the expected protein is undetectable by mass spectrometry.Histological analysis of Col6a3^(d3/d3)quadriceps revealed an abnormally high frequency of muscle cells with internally nucleated muscle cells,consistent with a myopathy phenotype.Interestingly,Col6a3^(d3/d3)mice are smaller in size,with their fat,muscle,and bone kept proportional compared to wild-type littermates.Conclusions:In summary,we performed the validation and preliminary phenotypic characterization of a novel Col6a3 knockout mouse model that could be further characterized and used to study COL6A3 biology and model collagen VI-associated diseases.展开更多
Dear Editor,Inclusion body myositis(IBM)is the most common idiopathic infl ammatory myopathy in adults over 50 years old[1,2].Th ere are no current Food and Drug Administration(FDA)-approved therapies and many unanswe...Dear Editor,Inclusion body myositis(IBM)is the most common idiopathic infl ammatory myopathy in adults over 50 years old[1,2].Th ere are no current Food and Drug Administration(FDA)-approved therapies and many unanswered questions regarding disease pathogenesis,course,and outcomes.We leveraged big data resources to conduct a retrospective analysis of IBM patient mortality among United States veterans.展开更多
In view of the enormous popularity of mass sporting events such as half-marathons, the number of patients with exertional rhabdomyolysis or exercise-induced heat stroke admitted to intensive care units(ICUs) has incre...In view of the enormous popularity of mass sporting events such as half-marathons, the number of patients with exertional rhabdomyolysis or exercise-induced heat stroke admitted to intensive care units(ICUs) has increased over the last decade. Because these patients have been reported to be at risk for malignant hyperthermia during general anesthesia, the intensive care community should bear in mind that the same risk of life-threatening rhabdomyolysis is present when these patients are admitted to an ICU, and volatile anesthetic sedation is chosen as the sedative technique. As illustrated by the three case studies we elaborate upon, a thorough diagnostic work-up is needed to clarify the subsequent risk of strenuous exercise, and the anesthetic exposure to volatile agents in these patients and their families. Other contraindications for the use of volatile intensive care sedation consist of known malignant hyperthermia susceptibility, congenital myopathies, Duchenne muscular dystrophy, and intracranial hypertension.展开更多
多发性肌炎（polymyositis，PM）和皮肌炎（dematomyositis，DM）均属特发性炎性肌病（idiopathic inflammatory myopathy，IIM）。此外，IIM还包括包涵体肌炎（inclusion body myositis，IBM）。目前认为PM和DM属于自身免疫性疾病，IB...多发性肌炎（polymyositis，PM）和皮肌炎（dematomyositis，DM）均属特发性炎性肌病（idiopathic inflammatory myopathy，IIM）。此外，IIM还包括包涵体肌炎（inclusion body myositis，IBM）。目前认为PM和DM属于自身免疫性疾病，IBM的免疫反应继发于骨骼肌细胞的退行性变。现主要介绍对PM和DM的一些认识。展开更多
Objective The present study is to observe in vitro the proliferation ability of the muscle cells from permanent myopathy （PM） patients of nomokalaemic periodic paralysis （normKPP）, which is caused by mutations of ...Objective The present study is to observe in vitro the proliferation ability of the muscle cells from permanent myopathy （PM） patients of nomokalaemic periodic paralysis （normKPP）, which is caused by mutations of Metl592Val in the skeletal muscle voltage gated sodium channel （SCN4A） gene on chromosome 17q23.1. We also evaluate the possible effect of the foreign basic fibroblast growth factor （bFGF） in preventing and curing PM. Methods The gastrocnemius muscle cells were taken from two male patients with PM of the same Chinese family with Metl592Val mutation of SCN4A, determined by gene screening. Four male patients suffering from the skeletal injury without PM were taken as control. All preparations were protogenerationally cultured in vitro. Proliferation of the cultured preparations was measured by MTT. Activities of the lactic dehydrogenase （LDH）, creatine kinase （CK）, and protein content in these cells were also detected. The effects of bFGF with different doses （10 ng/mL, 20 ng/mL, 40 ng/mL, 80 ng/mL, 120 ng/mL and 160 ng/mL） on the above mentioned parameters were also evaluated. Results Cells from both PM and control subjects were successfully cultured in vitro. The cultivation of the muscle cells from PM patients in vitro was not yet seen. Results indicated the obvious stimulation of bFGF on cell proliferation, activities of LDH and CK, protein synthesis, in a dose dependent manner. The optimal dose of bFGF was 120 ng/mL （P〈0.05）, beyond which greater dose caused a less effect. The effect of bFGF on 160 ng/mL was stronger than that on 80 ng/mL, but there was no significant difference （P〉0.05）. Conclusion Myoblastic cells from patients with PM had a weaker ability of developing into the myotubules, thus they were unable to perform effective regeneration, which resulted in a progressive necrosis. The exogenous bFGF could promote the division and proliferation of the muscle cells in vitro. These results shield a light on bFGF＇s potential role in preventing and treating PM.展开更多
Transcranial direct current stimulation (tDCS) has emerged as a nonpharmacological tool in physical rehabilitation. There have currently no studies that evaluated the safety and efficacy of tDCS in patients with derma...Transcranial direct current stimulation (tDCS) has emerged as a nonpharmacological tool in physical rehabilitation. There have currently no studies that evaluated the safety and efficacy of tDCS in patients with dermatomyositis. Case-report: Three adult women with dermatomyositis were allocated randomly to intervention (i-tDCS, one patient) or not (sham-tDCS, two patients) of three consecutive days of tDCS and evaluated in four periods: before-tDCS (PRE), 15 minutes after-tDCS (0th POST), 15 days after-tDCS (15th POST), and 30 days after-tDCS (30th POST). The tDCS was safe throughout the protocol, without disease relapsing or adverse effects related to tDCS. Furthermore, the tDCS increased the muscle torque and total work of dominant and non-dominant elbow flexors in the patient with i-tDCS, when compared to two patients with sham-tDCS. Conclusions: The tDCS was safe and appeared to influence long-term strength in the limb of the patient with stable dermatomyo-sitis.展开更多
文摘BACKGROUND Gastrointestinal(GI)manifestations are prevalent in genetic myopathies,posing significant diagnostic and management challenges.AIM To synthesize evidence on the diagnostic approaches,management strategies,patient perspectives,and future research directions regarding GI symptoms in genetic myopathies.METHODS A systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines.We searched PubMed,Scopus,EMBASE,and Web of Science from inception to December 2024.Eligible studies reported GI manifestations in genetic myopathies,including clinical evaluations,imaging,physiological tests,histopathology,and genetic analyses.Inclusion criteria encompassed original research studies,review articles,case reports,and clinical guidelines published in peer-reviewed journals.Exclusion criteria included conference abstracts without full-text availability and non-peer-reviewed sources.Two independent reviewers screened studies and extracted data.They assessed methodological quality using the Newcastle-Ottawa Scale for observational studies,A MeaSurement Tool to Assess Systematic Reviews for systematic reviews,and the Joanna Briggs Institute checklist for case reports.A systematic narrative synthesis was employed to summarize the findings.RESULTS A total of 234 studies met the inclusion criteria.GI manifestations varied widely,with dysphagia,gastroesophageal reflux,abdominal pain,constipation,diarrhea,and fecal incontinence being the most frequently reported symptoms.The included studies highlighted a multidisciplinary diagnostic approach incorporating clinical assessment,imaging,physiological testing,histopathology,and genetic testing.Management strategies ranged from dietary interventions and rehabilitative therapies to pharmacological treatments and surgical procedures.Patient perspectives underscored the significant impact of GI symptoms on quality of life,social interactions,and emotional well-being.The main limitations of the included studies were high heterogeneity in study design,small sample sizes,and the potential risk of bias due to limited methodological rigor in some reports.CONCLUSION This review underscores the complexity of GI manifestations in genetic myopathies and the need for a comprehensive,multidisciplinary management approach.Future research should focus on elucidating molecular mechanisms,identifying biomarkers,and developing targeted therapies to improve patient outcomes.The findings have implications for both clinical practice and public health,emphasizing the necessity of early diagnosis and personalized management strategies.
文摘Objective: To assess general pain and fatigue and their association with the disease status of patients with systemic autoimmune myopathies (SAMs), in terms of the impact of the COVID-19 pandemic on these parameters. Methods: This is a cross-sectional and prospective cohort study that included 72 patients with SAMs who were matched by age and gender with 67 healthy individuals. The patients engaged in an interview via a validity survey to measure disease status, and assess a visual analog scale (VAS) for pain and fatigue in two periods: before (phase I) and during (phase II) of the Brazilian COVID-19 pandemic. For cross-sectional analysis, patients’ data from phase I were compared to healthy individuals’ information, whereas for prospective analysis, data of the patients who were assessed in phase II were compared to the same patients’ data from phase I. Results: The patients had significantly more pain perception, comparable fatigue perception and fatigue severity, when compared to the healthy individuals. During the COVID-19 pandemic period, the disease activity, pain and fatigue perceptions, and fatigue severity remained unchanged. Despite this, the pain and fatigue perceptions correlated significantly with patients’ VAS, the patient health outcome, and fatigue severity. In addition, the pain perception correlated to creatine phosphokinase, whereas fatigue perceptions correlated to physicians' VAS. Conclusions: The study showed that patients with SAMs have significantly increased pain perceptions compared to healthy individuals. During the COVID-19 pandemic period, the pain and fatigue perceptions remained unchanged in patients with SAMs but they correlated to several disease status parameters.
文摘Background： Collagen Vl-related myopathies are autosomal dominant and recessive hereditary myopathies, mainly including Ullrich congenital muscular dystrophy （UCMD） and Bethlem myopathy （BM）. Muscle magnetic resonance imaging （MRI） has been widely used to diagnosis muscular disorders. The purpose of this study was to evaluate the diagnostic value of thigh muscles MRI for collagen VI-related myopathies. Methods： Eleven patients with collagen VI gene mutation-related myopathies were enrolled in this study. MRI of the thigh muscles was performed in all patients with collagen VI gene mutation-related myopathies and in 361 patients with other neuromuscular disorders （disease controls）. Tl-weighted images were used to assess fatty infiltration of the muscles using a modified Mercuri＇s scale. We assessed the sensitivity and specificity of the MRI features of collagen Vl-related myopathies. The relationship between fatty infiltration of muscles and specific collagen VI gene mutations was also investigated. Results： Eleven patients with collagen VI gene mutation-related rnyopathies included six UCMD patients and five BM patients. There was no significant difference between UCMD and BM patients in the fatty infiltration of each thigh muscle except sartorius （P = 0.033）： theretbre, we combined the UCMD and BM data. Mean fatty infiltration scores were 3.1 and 3.0 in adductor magnus and gluteus maximus, while the scores were 1.3, 1.3, and 1.5 in gracilis, adductor longus, and sartorius, respectively. A “target” sign in rectus femoris （RF） was present in seven cases, and a “sandwich” sign in vastus lateralis （VL） was present in ten cases. The “target” and “sandwich” signs had sensitivities of 63.6% and 90.9% and specificities of 97.3% and 96,9% for the diagnosis of collagen Vl-related myopathies, respectively. Fatty infiltration scores were 2.0-3.0 in seven patients with mutations in the triple-helical domain, and 1.0-1.5 in three of four patients with mutations in the N- or C-domain of the collagen VI genes. Conclusions： The “target” sign in RF and “sandwich” sign in VL are common MRI features and are useful for the diagnosis of collagen VI-related myopathies. The severity of fatty infiltration of muscles may have a relationship with the mutation location of collagen VI gene.
基金supported by grants from NHMRC(Grant No.1125514 and 2029334 to JRM,and 1120129 to JRM and CEH)National Heart Foundation of Australia(Vanguard-105720)+6 种基金the Victorian Government’s Operational Infrastructure Support Programsupported by a joint Baker Heart and Diabetes Institute-La Trobe University doctoral scholarshipsupported by Future Leader Fellowships from the National Heart Foundation of Australia(Grant No.102536 to EJH,102539 to KLW,and 102206 to ALG)supported by an Alice Baker and Eleanor Shaw Fellowship(The Baker Foundation,Australia)supported by a NHMRC Senior Research(Grant No.1078985)Baker Fellowship(The Baker Foundation,Australia)Cardiovascular Research Capacity Program-Research Leadership GrantsCardiovascular Research Capacity Program-Research Leadership Grants(NSW Health)。
文摘Background:Elucidating mechanisms underlying atrial myopathy,which predisposes individuals to atrial fibrillation(AF),will be critical for preventing/treating AF.In a serendipitous discovery,we identified atrial enlargement,fibrosis,and thrombi in mice with reduced phosphoinositide 3-kinase(PI3K)in cardiomyocytes.PI3K(p110a)is elevated in the heart with exercise and is critical for exercise-induced ventricular enlargement and protection,but the role in the atria was unknown.Physical inactivity and extreme endurance exercise can increase AF risk.Therefore,our objective was to investigate whether too little and/or too much PI3K alone induces cardiac pathology.Methods:New cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110a)activity were generated.Multi-omics was conducted in mouse atrial tissue,and lipidomics in human plasma.Results:Elevated PI3K led to an increase in heart size with preserved/enhanced function.Reduced PI3K led to atrial dysfunction,fibrosis,arrhythmia,increased susceptibility to atrial enlargement and thrombi,and dysregulation of monosialodihexosylganglioside(GM3),a lipid that regulates insulin-like growth factor-1(IGF1)-PI3K signaling.Proteomic profiling identified distinct signatures and signaling networks acrossatria with varying degrees of dysfunction,enlargement,and thrombi,including commonalities with the human AF proteome.PI3K-related lipids were dysregulated in plasma from athletes with AF.Conclusion:PI3K(p110a)is a critical regulator of atrial biology and function in mice.This work provides a proteomic resource of candidates for further validation as potential new drug targets and biomarkers for atrial myopathy.Further investigation of PI3K-related lipids as markers for identifying individuals at risk of AF is warranted.Dysregulation of PI3K may contribute to the association between increased cardiac risk with physical inactivity and extreme endurance exercise.
文摘BACKGROUND Mitochondrial myopathies are characterized by primary dysfunction of the mitochondrial respiratory chain;they typically present as chronic muscle weak-ness.Clinically visible acute respiratory dysfunctions associated with mito-chondrial myopathies occur rarely.CASE SUMMARY In this report,we present the case of a patient who developed postoperative hypoventilation after undergoing an uneventful administration of general anesthesia.A 34-year-old woman with no family history of myopathy underwent laparoscopic removal of a right-sided ureteric stone.Two days postoperatively,her oxygen saturation decreased rapidly,and blood gas analysis revealed hypercapnia.We promptly intubated and initiated the patient and initiated her on mechanical ventilation as she remained awake.Clinical examination findings were unremarkable;the results of laboratory investigations,including those for thyroid,hepatic,renal,and neuromuscular functions,were within normal limits.Muscle biopsy revealed muscle fibers of varying sizes as well as several dege-nerating and regenerating myofibers.Modified Gomori trichrome staining of the cross-sections revealed ragged red fibers.Based on these findings,we diagnosed the patient with mitochondrial myopathy.The patient’s condition gradually improved,and she was discharged on a home ventilator 73 days postoperatively.CONCLUSION Our case highlights that mitochondrial myopathy should be considered in the differential diagnosis of patients with postoperative respiratory failure.
基金supported by funding from the National Key Research and Development Program of China(2022YFF1100203)National Natural Science Foundation of China(32372349)+1 种基金Science and Technology Innovation Talent Project of Hunan Province(2022RC3056)Key Research and Development Program of Hunan Province(2024AQ2020)。
文摘Dexamethasone is a common glucocorticoid medication with adverse effects that can cause muscle atrophy,but no drug intervention has been approved or recommended for this condition.KF-8 is a rice bran-derived anti-oxidant peptide that extends the lifespan of Caenorhabditis elegans.We established a C.elegans model of dexamethasone-induced myopathy to evaluate the potential therapeutic effects of KF-8 in this model.C.elegans muscle function was assessed in terms of locomotory behaviors including crawling,swimming,burrowing,pharyngeal pumping,and head swing.Muscle actin filament integrity was evaluated using fluorescence imaging.The molecular mechanisms of KF-8 were investigated using transcriptome sequencing,quantitative real-time PCR(qRT-PCR),RNA interference,and Western blot analysis.Dexamethasone disrupted actin filaments in the striated muscles of the body wall and inhibited C.elegans crawling,swimming,burrowing,pharyngeal pumping,and head swing.KF-8 reversed the actin filament disruption and locomotor dysfunction induced by dexamethasone.Transcriptome sequencing,pathway enrichment,and qRT-PCR analyses revealed that KF-8 regulated the locomotion-related genes W04G5.10,vha-12,and ddr-1,as well as age-1(the catalytic subunit ortholog of phosphatidylinositol 3-kinase(PI3K)),and akt1.RNA interference,conducted using a genetically engineered Escherichia coli HT115 strain as a food source,confirmed age-1 as a key regulator of locomotor function of C.elegans.Further mechanistic studies with C2C12 myotubes showed that KF-8 regulated the IRS-PI3K-Akt pathway,the master regulator of protein synthesis and degradation.Together,these findings suggest that KF-8 protects against dexamethasoneinduced myopathy in C.elegans by regulating locomotion-related genes and the IRS-PI3K-Akt pathway.
文摘Background:Most mutations in the COL6A3 gene lead to collagen VI-related myopathies.This is due to a reduced expression or mislocalization of the COL6A3 protein.Therefore,studying the consequence of knocking out the Col6a3 gene in mouse models is relevant,but the Col6a3 mouse models reported so far do not entirely abolish COL6A3 protein expression.Methods:Here,we present the development,validation and preliminary phenotypic characterization of a novel CRISPR-based knockout mouse model targeting Col6a3 exon 3(Col6a3^(d3/d3)).Results:In this mouse model,Col6a3 mRNA is still expressed at a similar level to wild-type littermates,although the expected protein is undetectable by mass spectrometry.Histological analysis of Col6a3^(d3/d3)quadriceps revealed an abnormally high frequency of muscle cells with internally nucleated muscle cells,consistent with a myopathy phenotype.Interestingly,Col6a3^(d3/d3)mice are smaller in size,with their fat,muscle,and bone kept proportional compared to wild-type littermates.Conclusions:In summary,we performed the validation and preliminary phenotypic characterization of a novel Col6a3 knockout mouse model that could be further characterized and used to study COL6A3 biology and model collagen VI-associated diseases.
文摘Dear Editor,Inclusion body myositis(IBM)is the most common idiopathic infl ammatory myopathy in adults over 50 years old[1,2].Th ere are no current Food and Drug Administration(FDA)-approved therapies and many unanswered questions regarding disease pathogenesis,course,and outcomes.We leveraged big data resources to conduct a retrospective analysis of IBM patient mortality among United States veterans.
文摘In view of the enormous popularity of mass sporting events such as half-marathons, the number of patients with exertional rhabdomyolysis or exercise-induced heat stroke admitted to intensive care units(ICUs) has increased over the last decade. Because these patients have been reported to be at risk for malignant hyperthermia during general anesthesia, the intensive care community should bear in mind that the same risk of life-threatening rhabdomyolysis is present when these patients are admitted to an ICU, and volatile anesthetic sedation is chosen as the sedative technique. As illustrated by the three case studies we elaborate upon, a thorough diagnostic work-up is needed to clarify the subsequent risk of strenuous exercise, and the anesthetic exposure to volatile agents in these patients and their families. Other contraindications for the use of volatile intensive care sedation consist of known malignant hyperthermia susceptibility, congenital myopathies, Duchenne muscular dystrophy, and intracranial hypertension.
文摘多发性肌炎（polymyositis，PM）和皮肌炎（dematomyositis，DM）均属特发性炎性肌病（idiopathic inflammatory myopathy，IIM）。此外，IIM还包括包涵体肌炎（inclusion body myositis，IBM）。目前认为PM和DM属于自身免疫性疾病，IBM的免疫反应继发于骨骼肌细胞的退行性变。现主要介绍对PM和DM的一些认识。
文摘Objective The present study is to observe in vitro the proliferation ability of the muscle cells from permanent myopathy （PM） patients of nomokalaemic periodic paralysis （normKPP）, which is caused by mutations of Metl592Val in the skeletal muscle voltage gated sodium channel （SCN4A） gene on chromosome 17q23.1. We also evaluate the possible effect of the foreign basic fibroblast growth factor （bFGF） in preventing and curing PM. Methods The gastrocnemius muscle cells were taken from two male patients with PM of the same Chinese family with Metl592Val mutation of SCN4A, determined by gene screening. Four male patients suffering from the skeletal injury without PM were taken as control. All preparations were protogenerationally cultured in vitro. Proliferation of the cultured preparations was measured by MTT. Activities of the lactic dehydrogenase （LDH）, creatine kinase （CK）, and protein content in these cells were also detected. The effects of bFGF with different doses （10 ng/mL, 20 ng/mL, 40 ng/mL, 80 ng/mL, 120 ng/mL and 160 ng/mL） on the above mentioned parameters were also evaluated. Results Cells from both PM and control subjects were successfully cultured in vitro. The cultivation of the muscle cells from PM patients in vitro was not yet seen. Results indicated the obvious stimulation of bFGF on cell proliferation, activities of LDH and CK, protein synthesis, in a dose dependent manner. The optimal dose of bFGF was 120 ng/mL （P〈0.05）, beyond which greater dose caused a less effect. The effect of bFGF on 160 ng/mL was stronger than that on 80 ng/mL, but there was no significant difference （P〉0.05）. Conclusion Myoblastic cells from patients with PM had a weaker ability of developing into the myotubules, thus they were unable to perform effective regeneration, which resulted in a progressive necrosis. The exogenous bFGF could promote the division and proliferation of the muscle cells in vitro. These results shield a light on bFGF＇s potential role in preventing and treating PM.
基金Fundacao de Amparo a Pesquisa do Estado de Sao Paulo(FAPESP)#2019/12155-5 to RGMConselho Nacional de Desenvolvimento Cientifico e Tecnologico(CNPq)303379/2018-9 to SKSFaculdade de Medicina da USP to SKS.
文摘Transcranial direct current stimulation (tDCS) has emerged as a nonpharmacological tool in physical rehabilitation. There have currently no studies that evaluated the safety and efficacy of tDCS in patients with dermatomyositis. Case-report: Three adult women with dermatomyositis were allocated randomly to intervention (i-tDCS, one patient) or not (sham-tDCS, two patients) of three consecutive days of tDCS and evaluated in four periods: before-tDCS (PRE), 15 minutes after-tDCS (0th POST), 15 days after-tDCS (15th POST), and 30 days after-tDCS (30th POST). The tDCS was safe throughout the protocol, without disease relapsing or adverse effects related to tDCS. Furthermore, the tDCS increased the muscle torque and total work of dominant and non-dominant elbow flexors in the patient with i-tDCS, when compared to two patients with sham-tDCS. Conclusions: The tDCS was safe and appeared to influence long-term strength in the limb of the patient with stable dermatomyo-sitis.
