Seeking candidate variants of arrhythmogenic cardiomyopathy in sarcomere genes

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.

Functional Analysis of Slow Myosin Heavy Chain 1 and Myomesin-3 in Sarcomere Organization in Zebrafish Embryonic Slow Muscles

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.

Smyd1 is essential for myosin expression and sarcomere organization in craniofacial,extraocular,and cardiac muscles

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.

Contractile apparatus dysfunction early in the pathophysiology of diabetic 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.

Pediatric restrictive cardiomyopathy due to a heterozygous mutation of the TNNI3 gene

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.