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
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
Skeletal muscle is the source of human body motion.Many scholars have been studying in this field to reveal its contraction mechanism,and relevant achievements have been awarded the Nobel Prize.This paper reviewed the...Skeletal muscle is the source of human body motion.Many scholars have been studying in this field to reveal its contraction mechanism,and relevant achievements have been awarded the Nobel Prize.This paper reviewed the current researches on biomechanics of skeletal muscle,and concluded two strategies(top-down and bottom-up methods) for the biomechanical research of skeletal muscle.Moreover,this paper generalized two major aspects of muscle research:(1) the multi-force coupling mechanism and the collective operation mechanism of molecular motors;(2) the bioelectrochemical driving and control principium of muscle contraction.We discussed the solution for experimental verification and induced a novel idea to study the biomechanics of skeletal muscle based on the microscopic working mechanism of molecular motor,which is the origin of muscle contraction.Finally we analyzed the disadvantages in existent researches and explored future directions that need further studies.展开更多
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 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.
基金supported by the National Key Research and Development Program of the Ministry of Science and Technology of China (No. 2018YFF0300405)the Fundamental Research Fund for Central Universities of China (No. 2022YB013)。
基金supported by the National Natural Science Foundation of China(61075101,60643002)the National Basic Research Program of China(2011CB013203)the Science and Technology Intercrossing and the Medical and Technology Intercrossing Research Foundation of Shanghai Jiao Tong University(LG2011ZD106,YG2010ZD101)
文摘Skeletal muscle is the source of human body motion.Many scholars have been studying in this field to reveal its contraction mechanism,and relevant achievements have been awarded the Nobel Prize.This paper reviewed the current researches on biomechanics of skeletal muscle,and concluded two strategies(top-down and bottom-up methods) for the biomechanical research of skeletal muscle.Moreover,this paper generalized two major aspects of muscle research:(1) the multi-force coupling mechanism and the collective operation mechanism of molecular motors;(2) the bioelectrochemical driving and control principium of muscle contraction.We discussed the solution for experimental verification and induced a novel idea to study the biomechanics of skeletal muscle based on the microscopic working mechanism of molecular motor,which is the origin of muscle contraction.Finally we analyzed the disadvantages in existent researches and explored future directions that need further studies.
