The first in vivo measurements of serial sarcomere number in human muscles before and after eccentric strength training have just been published and the results will interest anyone involved with sport or health:Train...The first in vivo measurements of serial sarcomere number in human muscles before and after eccentric strength training have just been published and the results will interest anyone involved with sport or health:Training the hamstrings 3 times per week for 9 weeks with the Nordic hamstring exercise was found to increase the number of sarcomeres in series in the biceps femoris long head(BFlh)by≥25%.1 In this commentary,we highlight an additional,paradoxical finding,which was not discussed by the authors;namely that the substantial serial sarcomere addition must have been accompanied by a subtraction of sarcomeres in parallel to match the relatively small increase in muscle volume after training.展开更多
Sarcomerogenesis,the addition of serial sarcomeres in skeletal muscle myofibrils and fibres,is a natural occurrence during growth and maturation of animals,including humans.However,the detailed mechanisms that allow f...Sarcomerogenesis,the addition of serial sarcomeres in skeletal muscle myofibrils and fibres,is a natural occurrence during growth and maturation of animals,including humans.However,the detailed mechanisms that allow for sarcomerogenesis are not fully understood.In some diseases,such as cerebral palsy in children,sarcomerogenesis appears to be inhibited or at least reduced,1,2 often causing severe restrictions in muscle and joint function.展开更多
Hypertrophic cardiomyopathy(HCM)is a major contributor to cardiovascular diseases(CVD),the leading cause of death globally.HCM can precipitate heart failure(HF)by causing the cardiac tissue to weaken and stretch,there...Hypertrophic cardiomyopathy(HCM)is a major contributor to cardiovascular diseases(CVD),the leading cause of death globally.HCM can precipitate heart failure(HF)by causing the cardiac tissue to weaken and stretch,thereby impairing its pumping efficiency.Moreover,HCM increases the risk of atrial fibrillation,which in turn elevates the likelihood of thrombus formation and stroke.Given these significant clinical ramifications,research into the etiology and pathogenesis of HCM is intensifying at multiple levels.In this review,we discuss and synthesize the latest findings on HCM pathogenesis,drawing on key experimental studies conducted both in vitro and in vivo.We also offer our insights and perspectives on these mechanisms,while highlighting the limitations of current research.Advancing fundamental research in this area is essential for developing effective therapeutic interventions and enhancing the clinical management of HCM.展开更多
Hypertrophic cardiomyopathy(HCM)is the most common genetic cardiovascular disease,mostly inherited in an autosomal dominant manner.It is a global heart disease with complex clinical phenotypes and gene expression.The ...Hypertrophic cardiomyopathy(HCM)is the most common genetic cardiovascular disease,mostly inherited in an autosomal dominant manner.It is a global heart disease with complex clinical phenotypes and gene expression.The prevalence rate in the population is 1:500-1:200.This article mainly introduces the diagnostic criteria,pathological manifestations,and genetic basis of HCM,which is the leading cause of sudden death in adolescents and athletes due to exercise,with 60%-70%showing familial clustering.It also discusses the latest progress in the relationship between different genotypes and clinical phenotypes of HCM pa-tients.展开更多
Background Serial sarcomere number(SSN)critically influences muscle function and is hypothesized to protect against injury.While most evidence for SSN addition comes from non-human animal studies,eccentric exercise is...Background Serial sarcomere number(SSN)critically influences muscle function and is hypothesized to protect against injury.While most evidence for SSN addition comes from non-human animal studies,eccentric exercise is often proposed as a key stimulus due to its association with increased fascicle length in humans.However,the most efficient exercise stimuli and the effectiveness of eccentric training in increasing SSN remain unclear.The objective of this study was to provide a detailed historical overview of research exploring the mechanical factors regulating muscle/fiber length and its relationship with function,and to explore more recent evidence that eccentric muscle contractions might be an important stimulus for SSN regulation using a meta-analytic approach.Methods An extensive literature search with snowballing was conducted to build the historical review.A systematic review with random-effect meta analyses was performed to compare proposed types of fiber-lengthening exercises to control conditions.Results The historical review demonstrated that the application of forces at long fiber lengths,but not specifically the use of greater excursions,plays an important role in increasing SSN.Animal data showed changes in SSN exceeding 20%over several weeks with varied forms of activities.Nonetheless,the meta-analysis revealed a lack of effect of eccentric resistance training in animal models(Δ=1%;Cohen’s d=0.19(95%confidence interval:–0.29 to 0.67),p=0.449).Conclusion High active or passive muscle forces applied at long fiber lengths appear to be the key stimuli triggering sarcomerogenesis.Eccentric exercise does not seem to be a key promoter of SSN.Too few studies exist to draw conclusions as to the effect of eccentric exercise on SSN in humans.Understanding the mechanical triggers and physiological mechanisms involved in serial sarcomere addition could help in the development of exercise(and other)interventions to optimize muscle function and reduce injury risk.展开更多
The maximal force a muscle can exert depends on its length,which has been explained by the sliding filament theory on the sarcomere level.1 A longer muscle can act over a greater range of motion and has more sarcomere...The maximal force a muscle can exert depends on its length,which has been explained by the sliding filament theory on the sarcomere level.1 A longer muscle can act over a greater range of motion and has more sarcomeres in series,which increases its capacity to produce force at a specific muscle contraction velocity because each sarcomere contracts at a lower velocity.展开更多
Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure in patients.Independent of hypertension and coronary artery disease,diabetes is associated with a specific cardiomyopathy,...Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure in patients.Independent of hypertension and coronary artery disease,diabetes is associated with a specific cardiomyopathy,known as diabetic cardiomyopathy(DCM).Four decades of research in experimental animal models and advances in clinical imaging techniques suggest that DCM is a progressive disease,beginning early after the onset of type 1 and type 2 diabetes,ahead of left ventricular remodeling and overt diastolic dysfunction.Although the molecular pathogenesis of early DCM still remains largely unclear,activation of protein kinase C appears to be central in driving the oxidative stress dependent and independent pathways in the development of contractile dysfunction.Multiple subcellular alterations to the cardiomyocyte are now being highlighted as critical events in the early changes to the rate of force development,relaxation and stability under pathophysiological stresses.These changes include perturbed calcium handling,suppressed activity of aerobic energy producing enzymes,altered transcriptional and posttranslational modification of membrane and sarcomeric cytoskeletal proteins,reduced actin-myosin cross-bridge cycling and dynamics,and changed myofilament calcium sensitivity.In this review,we will present and discuss novel aspects of the molecular pathogenesis of early DCM,with a special focus on the sarcomeric contractile apparatus.展开更多
Myofibrillogenesis, the process of sarcomere formation, requires close interactions of sarcomeric proteins and various components of sarcomere structures. The myosin thick filaments and M-lines are two key components ...Myofibrillogenesis, the process of sarcomere formation, requires close interactions of sarcomeric proteins and various components of sarcomere structures. The myosin thick filaments and M-lines are two key components of the sarcomere. It has been suggested that myomesin proteins of M-lines interact with myosin and titin proteins and keep the thick and titin filaments in order. However, the function of myomesin in myofibrillogenesis and sarcomere organization remained largely enigmatic. No knockout or knockdown animal models have been reported to elucidate the role of myomesin in sarcomere organization in vivo. In this study, by using the gene-specific knockdown approach in zebrafish embryos, we carded out a loss-of-function analysis of myomesin-3 and slow myosin heavy chain 1 （smyhcl） expressed specifically in slow muscles. We demonstrated that knockdown of smyhcl abolished the sarcomeric localization of myomesin-3 in slow muscles. In contrast, loss of myomesin-3 had no effect on the sarcomeric organization of thick and thin filaments as well as M- and Z-line structures. Together, these studies indicate that myosin thick filaments are required for M-line organization and M-line localization of myomesin-3. In contrast, myomesin-3 is dispensable for sarcomere organization in slow muscles.展开更多
Pediatric cardiomyopathies are clinically heterogeneous heart muscle disorders that are responsible for significant morbidity and mortality. Phenotypes include hypertrophic cardiomyopathy, dilated cardiomyopathy, rest...Pediatric cardiomyopathies are clinically heterogeneous heart muscle disorders that are responsible for significant morbidity and mortality. Phenotypes include hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, left ventricular noncompaction and arrhythmogenic right ventricular cardiomyopathy. There is substantial evidence for a genetic contribution to pediatric cardiomyopathy. To date, more than 100 genes have been implicated in cardiomyopathy, but comprehensive genetic diagnosis has been problematic because of the large number of genes, the private nature of mutations, and difficulties in interpreting novel rare variants. This review will focus on current knowledge on the genetic etiologies of pediatric cardiomyopathy and their diagnostic relevance in clinical settings. Recent developments in sequencing technologies are greatly impacting the pace of gene discovery and clinical diagnosis. Understanding the genetic basis for pediatric cardiomyopathy and establishing genotypephenotype correlations may help delineate the molecular and cellular events necessary to identify potential novel therapeutic targets for heart muscle dysfunction in children.展开更多
Pediatric restrictive cardiomyopathy is rare and most commonly idiopathic in origin. Here, we applied a candi- date gene approach and identified a missense mutation in the cardiac troponin I gene in a 12-year-old Chin...Pediatric restrictive cardiomyopathy is rare and most commonly idiopathic in origin. Here, we applied a candi- date gene approach and identified a missense mutation in the cardiac troponin I gene in a 12-year-old Chinese girl with restrictive cardiomyopathy. This study indicates that mutation in sarcomere protein genes may play an im- portant role in idiopathic pediatric restrictive cardiomyopathy.展开更多
Skeletal and cardiac muscles are striated myofibers that contain highly organized sarcomeres for muscle contraction.Recent studies revealed that Smyd1,a lysine methyltransferase,plays a key role in sarcomere assembly ...Skeletal and cardiac muscles are striated myofibers that contain highly organized sarcomeres for muscle contraction.Recent studies revealed that Smyd1,a lysine methyltransferase,plays a key role in sarcomere assembly in heart and trunk skeletal muscles.However,Smyd1 expression and function in craniofacial muscles are not known.Here,we analyze the developmental expression and function of two smyd1 paralogous genes,smyd1 a and smyd1 b,in craniofacial and cardiac muscles of zebrafish embryos.Our data show that loss of smyd1a(smyd1a^(mb5))or smyd1b(smyd1b^(sa15678))has no visible effects on myogenic commitment and expression of myod and myosin heavy-chain m RNA transcripts in craniofacial muscles.However,myosin heavy-chain protein accumulation and sarcomere organization are dramatically reduced in smyd1b^(sa15678) single mutant,and almost completely diminish in smyd1a^(mb5);smyd1b^(sa15678) double mutant,but not in smyd1a^(mb5) mutant.Similar defects are also observed in cardiac muscles of smyd1b^(sa15678) mutant.Defective craniofacial and cardiac muscle formation is associated with an upregulation of hsp90α1 and unc45b mRNA expression in smyd1b^(sa15678) and smyd1a^(mb5);smyd1b^(sa15678) mutants.Together,our studies indicate that Smyd1b,but not Smyd1a,plays a key role in myosin heavy-chain protein expression and sarcomere organization in craniofacial and cardiac muscles.Loss of smyd1b results in muscle-specific stress response.展开更多
ObjectiveTo seek potential pathogenic variants in sarcomere genes in arrhythmogenic cardiomyopathy(ACM)and describe the characteristics.Methods and Results We performed targeted sequencing of 14sarcomere genes in 118 ...ObjectiveTo seek potential pathogenic variants in sarcomere genes in arrhythmogenic cardiomyopathy(ACM)and describe the characteristics.Methods and Results We performed targeted sequencing of 14sarcomere genes in 118 cases with the clinical diagnosis of ARVC and Sanger sequencing of the specific variants in family members of the probands.展开更多
Titin,the largest known protein in nature,is a giant sarcomeric protein that plays essential architectural,developmental,and regulatory roles in striated muscles.Mutations in the TTN gene(MIM:188840)that encodes titin...Titin,the largest known protein in nature,is a giant sarcomeric protein that plays essential architectural,developmental,and regulatory roles in striated muscles.Mutations in the TTN gene(MIM:188840)that encodes titin are related to a broad range of muscle diseases known as titinopathies,with diverse clinical manifestations including weakness,contractures,scoliosis,respiratory failure,and cardiomyopathy.1 In this case report,we describe two sisters with severe scoliosis,both carrying novel compound heterozygous variants in the TTN gene,yet presenting distinct clinical phenotypes,adding to the growing body of evidence linking TTN mutations to scoliosis and other titinrelated disorders.展开更多
Hypertrophic cardiomyopathy(HCM)is one of the most common inherited cardiovascular diseases,with a global prevalence estimated at 0.2%to 0.5%.1 It is characterized by left ventricular hypertrophy which could not be ex...Hypertrophic cardiomyopathy(HCM)is one of the most common inherited cardiovascular diseases,with a global prevalence estimated at 0.2%to 0.5%.1 It is characterized by left ventricular hypertrophy which could not be explained by abnormal loading conditions,and a considerable proportion of patients were accompanied by either resting or inducible left ventricular outflow tract(LVOT)obstruction,leading to impaired cardiac function,mitral regurgitation due to systolic anterior motion(SAM)condition,with subsequent reduced quality of life,adverse clinical outcomes or even sudden death(Supplementary Text 1 online).2 HCM was previously believed to exhibit an autosomal dominant inheritance pattern,typically caused by pathogenic mutations in genes encoding sarcomeric proteins,with MYBPC3 and MYH7 being the most commonly involved genes.3 However,about 60%of all patients test negative for sarcomeric variants,4 suggesting a possible polygenic inheritance pattern in these patients and the contribution of non-genetic factors on disease phenotype(Supplementary Text 2 online).展开更多
A non-equilibrium statistical method is used to study the collective characteristics of myosin II motors in a sarcomere during its contraction. By means of Fokker-Planck equation of molecular motors, we present a dyna...A non-equilibrium statistical method is used to study the collective characteristics of myosin II motors in a sarcomere during its contraction. By means of Fokker-Planck equation of molecular motors, we present a dynamic mechanical model for the sarcomere in skeletal muscle. This model has been solved with a numerical algorithm based on experimental chemical transition rates. The influences of ATP concentration and load on probability density, contraction velocity and maximum active force are discussed respectively. It is shown that contraction velocity and maximum isometric active force increase with the increasing ATP concentration and become constant when the ATP concentration reaches equilibrium saturation. Contraction velocity reduces gradually as the load force increases. We also find that active force begins to increase then decrease with the increasing length of sarcomere, and has a maximum value at the optimal length that all myosin motors can attach to actin filament. Our results are in good agreement with the Hill muscle model.展开更多
文摘The first in vivo measurements of serial sarcomere number in human muscles before and after eccentric strength training have just been published and the results will interest anyone involved with sport or health:Training the hamstrings 3 times per week for 9 weeks with the Nordic hamstring exercise was found to increase the number of sarcomeres in series in the biceps femoris long head(BFlh)by≥25%.1 In this commentary,we highlight an additional,paradoxical finding,which was not discussed by the authors;namely that the substantial serial sarcomere addition must have been accompanied by a subtraction of sarcomeres in parallel to match the relatively small increase in muscle volume after training.
文摘Sarcomerogenesis,the addition of serial sarcomeres in skeletal muscle myofibrils and fibres,is a natural occurrence during growth and maturation of animals,including humans.However,the detailed mechanisms that allow for sarcomerogenesis are not fully understood.In some diseases,such as cerebral palsy in children,sarcomerogenesis appears to be inhibited or at least reduced,1,2 often causing severe restrictions in muscle and joint function.
基金supported by Henan Provincial Key Technologies R&D Program(Grant No.25202310242)Henan Provincial Medical Science and Technology Tackling Program(Grant No.LHGJ20240150).
文摘Hypertrophic cardiomyopathy(HCM)is a major contributor to cardiovascular diseases(CVD),the leading cause of death globally.HCM can precipitate heart failure(HF)by causing the cardiac tissue to weaken and stretch,thereby impairing its pumping efficiency.Moreover,HCM increases the risk of atrial fibrillation,which in turn elevates the likelihood of thrombus formation and stroke.Given these significant clinical ramifications,research into the etiology and pathogenesis of HCM is intensifying at multiple levels.In this review,we discuss and synthesize the latest findings on HCM pathogenesis,drawing on key experimental studies conducted both in vitro and in vivo.We also offer our insights and perspectives on these mechanisms,while highlighting the limitations of current research.Advancing fundamental research in this area is essential for developing effective therapeutic interventions and enhancing the clinical management of HCM.
基金Supported by National Natural Science Foundation of China,No.82230065,No.82371974 and No.82272009.
文摘Hypertrophic cardiomyopathy(HCM)is the most common genetic cardiovascular disease,mostly inherited in an autosomal dominant manner.It is a global heart disease with complex clinical phenotypes and gene expression.The prevalence rate in the population is 1:500-1:200.This article mainly introduces the diagnostic criteria,pathological manifestations,and genetic basis of HCM,which is the leading cause of sudden death in adolescents and athletes due to exercise,with 60%-70%showing familial clustering.It also discusses the latest progress in the relationship between different genotypes and clinical phenotypes of HCM pa-tients.
文摘Background Serial sarcomere number(SSN)critically influences muscle function and is hypothesized to protect against injury.While most evidence for SSN addition comes from non-human animal studies,eccentric exercise is often proposed as a key stimulus due to its association with increased fascicle length in humans.However,the most efficient exercise stimuli and the effectiveness of eccentric training in increasing SSN remain unclear.The objective of this study was to provide a detailed historical overview of research exploring the mechanical factors regulating muscle/fiber length and its relationship with function,and to explore more recent evidence that eccentric muscle contractions might be an important stimulus for SSN regulation using a meta-analytic approach.Methods An extensive literature search with snowballing was conducted to build the historical review.A systematic review with random-effect meta analyses was performed to compare proposed types of fiber-lengthening exercises to control conditions.Results The historical review demonstrated that the application of forces at long fiber lengths,but not specifically the use of greater excursions,plays an important role in increasing SSN.Animal data showed changes in SSN exceeding 20%over several weeks with varied forms of activities.Nonetheless,the meta-analysis revealed a lack of effect of eccentric resistance training in animal models(Δ=1%;Cohen’s d=0.19(95%confidence interval:–0.29 to 0.67),p=0.449).Conclusion High active or passive muscle forces applied at long fiber lengths appear to be the key stimuli triggering sarcomerogenesis.Eccentric exercise does not seem to be a key promoter of SSN.Too few studies exist to draw conclusions as to the effect of eccentric exercise on SSN in humans.Understanding the mechanical triggers and physiological mechanisms involved in serial sarcomere addition could help in the development of exercise(and other)interventions to optimize muscle function and reduce injury risk.
文摘The maximal force a muscle can exert depends on its length,which has been explained by the sliding filament theory on the sarcomere level.1 A longer muscle can act over a greater range of motion and has more sarcomeres in series,which increases its capacity to produce force at a specific muscle contraction velocity because each sarcomere contracts at a lower velocity.
基金The research funding from the International Synchrotron Access Program(AS/IA133)of the Australian Synchrotron(to Pearson JT)A Grant-in-Aid for Scientific Research(#E056,26670413)from the Ministry of Education,Culture,Sports,Sciences and Technology of Japan(to Shirai M)
文摘Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure in patients.Independent of hypertension and coronary artery disease,diabetes is associated with a specific cardiomyopathy,known as diabetic cardiomyopathy(DCM).Four decades of research in experimental animal models and advances in clinical imaging techniques suggest that DCM is a progressive disease,beginning early after the onset of type 1 and type 2 diabetes,ahead of left ventricular remodeling and overt diastolic dysfunction.Although the molecular pathogenesis of early DCM still remains largely unclear,activation of protein kinase C appears to be central in driving the oxidative stress dependent and independent pathways in the development of contractile dysfunction.Multiple subcellular alterations to the cardiomyocyte are now being highlighted as critical events in the early changes to the rate of force development,relaxation and stability under pathophysiological stresses.These changes include perturbed calcium handling,suppressed activity of aerobic energy producing enzymes,altered transcriptional and posttranslational modification of membrane and sarcomeric cytoskeletal proteins,reduced actin-myosin cross-bridge cycling and dynamics,and changed myofilament calcium sensitivity.In this review,we will present and discuss novel aspects of the molecular pathogenesis of early DCM,with a special focus on the sarcomeric contractile apparatus.
基金supported by a research grant(MB-8716-08) from United States-Israel Binational Agriculture Research and Development Fund to SJD and a NIH grant(DA14546) to SCELiangyi Xue was supported by a Pao Yu-Kong and Pao Zhao-Long Scholarship for Chinese Scholars Studying Abroad from Ningbo University,China
文摘Myofibrillogenesis, the process of sarcomere formation, requires close interactions of sarcomeric proteins and various components of sarcomere structures. The myosin thick filaments and M-lines are two key components of the sarcomere. It has been suggested that myomesin proteins of M-lines interact with myosin and titin proteins and keep the thick and titin filaments in order. However, the function of myomesin in myofibrillogenesis and sarcomere organization remained largely enigmatic. No knockout or knockdown animal models have been reported to elucidate the role of myomesin in sarcomere organization in vivo. In this study, by using the gene-specific knockdown approach in zebrafish embryos, we carded out a loss-of-function analysis of myomesin-3 and slow myosin heavy chain 1 （smyhcl） expressed specifically in slow muscles. We demonstrated that knockdown of smyhcl abolished the sarcomeric localization of myomesin-3 in slow muscles. In contrast, loss of myomesin-3 had no effect on the sarcomeric organization of thick and thin filaments as well as M- and Z-line structures. Together, these studies indicate that myosin thick filaments are required for M-line organization and M-line localization of myomesin-3. In contrast, myomesin-3 is dispensable for sarcomere organization in slow muscles.
基金Supported by The Children’s Cardiomyopathy FoundationCincinnati Children’s Hospital’s Clinical and Translational Science Award,No.NIH-ULl RR026314(Ware SM)and AHA Postdoctoral Fellowship Award,No.12POST10370002(Tariq M)
文摘Pediatric cardiomyopathies are clinically heterogeneous heart muscle disorders that are responsible for significant morbidity and mortality. Phenotypes include hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, left ventricular noncompaction and arrhythmogenic right ventricular cardiomyopathy. There is substantial evidence for a genetic contribution to pediatric cardiomyopathy. To date, more than 100 genes have been implicated in cardiomyopathy, but comprehensive genetic diagnosis has been problematic because of the large number of genes, the private nature of mutations, and difficulties in interpreting novel rare variants. This review will focus on current knowledge on the genetic etiologies of pediatric cardiomyopathy and their diagnostic relevance in clinical settings. Recent developments in sequencing technologies are greatly impacting the pace of gene discovery and clinical diagnosis. Understanding the genetic basis for pediatric cardiomyopathy and establishing genotypephenotype correlations may help delineate the molecular and cellular events necessary to identify potential novel therapeutic targets for heart muscle dysfunction in children.
基金funded by the Natural Science Foundation of China (No.81000076)the Youth Education Program to Shi-wei YANG supported by Nanjing Health Bureau
文摘Pediatric restrictive cardiomyopathy is rare and most commonly idiopathic in origin. Here, we applied a candi- date gene approach and identified a missense mutation in the cardiac troponin I gene in a 12-year-old Chinese girl with restrictive cardiomyopathy. This study indicates that mutation in sarcomere protein genes may play an im- portant role in idiopathic pediatric restrictive cardiomyopathy.
基金supported by funding from the U.S.National Institute of Health(NIH)National Institute of Arthritis and Musculoskeletal and Skin Diseases(R01AR072703 to S.Du)supported in part by fellowships from the China Scholarship Council。
文摘Skeletal and cardiac muscles are striated myofibers that contain highly organized sarcomeres for muscle contraction.Recent studies revealed that Smyd1,a lysine methyltransferase,plays a key role in sarcomere assembly in heart and trunk skeletal muscles.However,Smyd1 expression and function in craniofacial muscles are not known.Here,we analyze the developmental expression and function of two smyd1 paralogous genes,smyd1 a and smyd1 b,in craniofacial and cardiac muscles of zebrafish embryos.Our data show that loss of smyd1a(smyd1a^(mb5))or smyd1b(smyd1b^(sa15678))has no visible effects on myogenic commitment and expression of myod and myosin heavy-chain m RNA transcripts in craniofacial muscles.However,myosin heavy-chain protein accumulation and sarcomere organization are dramatically reduced in smyd1b^(sa15678) single mutant,and almost completely diminish in smyd1a^(mb5);smyd1b^(sa15678) double mutant,but not in smyd1a^(mb5) mutant.Similar defects are also observed in cardiac muscles of smyd1b^(sa15678) mutant.Defective craniofacial and cardiac muscle formation is associated with an upregulation of hsp90α1 and unc45b mRNA expression in smyd1b^(sa15678) and smyd1a^(mb5);smyd1b^(sa15678) mutants.Together,our studies indicate that Smyd1b,but not Smyd1a,plays a key role in myosin heavy-chain protein expression and sarcomere organization in craniofacial and cardiac muscles.Loss of smyd1b results in muscle-specific stress response.
文摘ObjectiveTo seek potential pathogenic variants in sarcomere genes in arrhythmogenic cardiomyopathy(ACM)and describe the characteristics.Methods and Results We performed targeted sequencing of 14sarcomere genes in 118 cases with the clinical diagnosis of ARVC and Sanger sequencing of the specific variants in family members of the probands.
基金supported by the National Natural Science Foundation of China(No.82272446).
文摘Titin,the largest known protein in nature,is a giant sarcomeric protein that plays essential architectural,developmental,and regulatory roles in striated muscles.Mutations in the TTN gene(MIM:188840)that encodes titin are related to a broad range of muscle diseases known as titinopathies,with diverse clinical manifestations including weakness,contractures,scoliosis,respiratory failure,and cardiomyopathy.1 In this case report,we describe two sisters with severe scoliosis,both carrying novel compound heterozygous variants in the TTN gene,yet presenting distinct clinical phenotypes,adding to the growing body of evidence linking TTN mutations to scoliosis and other titinrelated disorders.
基金supported by the National Natural Science Foundation of China(82460073)the National Key Research and Development Program(2022YFC2503400)+1 种基金the Major Science and Technology Special Plan Project of Yunnan Province(202302AA310045)the Talent Trusteeship Program of Fuwai Yunnan Hospital(2024RCTJ-QN008).
文摘Hypertrophic cardiomyopathy(HCM)is one of the most common inherited cardiovascular diseases,with a global prevalence estimated at 0.2%to 0.5%.1 It is characterized by left ventricular hypertrophy which could not be explained by abnormal loading conditions,and a considerable proportion of patients were accompanied by either resting or inducible left ventricular outflow tract(LVOT)obstruction,leading to impaired cardiac function,mitral regurgitation due to systolic anterior motion(SAM)condition,with subsequent reduced quality of life,adverse clinical outcomes or even sudden death(Supplementary Text 1 online).2 HCM was previously believed to exhibit an autosomal dominant inheritance pattern,typically caused by pathogenic mutations in genes encoding sarcomeric proteins,with MYBPC3 and MYH7 being the most commonly involved genes.3 However,about 60%of all patients test negative for sarcomeric variants,4 suggesting a possible polygenic inheritance pattern in these patients and the contribution of non-genetic factors on disease phenotype(Supplementary Text 2 online).
基金supported by the National Natural Science Foundation of China (Grant No. 61075101/60643002)the Research Fund of State Key Laboratory of MSV, China (Grant No. MSV-2010-1)+2 种基金the National High-Tech Research and Development Program of China (Grant No. 2006AA04Z240)the Shanghai Dawn Program (Grant No. 07SG14)the Medical and Technology Intercrossing Research Foundation of Shanghai Jiao Tong University (Grant No. YG2010ZD101)
文摘A non-equilibrium statistical method is used to study the collective characteristics of myosin II motors in a sarcomere during its contraction. By means of Fokker-Planck equation of molecular motors, we present a dynamic mechanical model for the sarcomere in skeletal muscle. This model has been solved with a numerical algorithm based on experimental chemical transition rates. The influences of ATP concentration and load on probability density, contraction velocity and maximum active force are discussed respectively. It is shown that contraction velocity and maximum isometric active force increase with the increasing ATP concentration and become constant when the ATP concentration reaches equilibrium saturation. Contraction velocity reduces gradually as the load force increases. We also find that active force begins to increase then decrease with the increasing length of sarcomere, and has a maximum value at the optimal length that all myosin motors can attach to actin filament. Our results are in good agreement with the Hill muscle model.
