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Comprehensive Physiology Jun 2017Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere,... (Review)
Review
Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold to maintain cellular integrity are the intermediate filaments. The costamere, on the other hand, tethers the sarcomere to the cell membrane. Unique structures like the intercalated disc in cardiac muscle and the myotendinous junction in skeletal muscle help synchronize and transmit force. Intense investigation has been done on many of the proteins that make up these cytoskeletal assemblies. Yet the details of their function and how they interconnect have just started to be elucidated. A vast number of human myopathies are contributed to mutations in muscle proteins; thus understanding their basic function provides a mechanistic understanding of muscle disorders. In this review, we highlight the components of striated muscle with respect to their interactions, signaling pathways, functions, and connections to disease. © 2017 American Physiological Society. Compr Physiol 7:891-944, 2017.
Topics: Actins; Animals; Cytoskeleton; Humans; Muscle Contraction; Myosins; Sarcomeres
PubMed: 28640448
DOI: 10.1002/cphy.c160033 -
Nature Reviews. Cardiology Jun 2022Variants in >12 genes encoding sarcomeric proteins can cause various cardiomyopathies. The two most common are hypertrophic cardiomyopathy (HCM) and dilated... (Review)
Review
Variants in >12 genes encoding sarcomeric proteins can cause various cardiomyopathies. The two most common are hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Current therapeutics do not target the root causes of these diseases, but attempt to prevent disease progression and/or to manage symptoms. Accordingly, novel approaches are being developed to treat the cardiac muscle dysfunction directly. Challenges to developing therapeutics for these diseases include the diverse mechanisms of pathogenesis, some of which are still being debated and defined. Four small molecules that modulate the myosin motor protein in the cardiac sarcomere have shown great promise in the settings of HCM and DCM, regardless of the underlying genetic pathogenesis, and similar approaches are being developed to target other components of the sarcomere. In the setting of HCM, mavacamten and aficamten bind to the myosin motor and decrease the ATPase activity of myosin. In the setting of DCM, omecamtiv mecarbil and danicamtiv increase myosin activity in cardiac muscle (but omecamtiv mecarbil decreases myosin activity in vitro). In this Review, we discuss the therapeutic strategies to alter sarcomere contractile activity and summarize the data indicating that targeting one protein in the sarcomere can be effective in treating patients with genetic variants in other sarcomeric proteins, as well as in patients with non-sarcomere-based disease.
Topics: Cardiomyopathies; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Humans; Mutation; Myocardium; Myosins; Sarcomeres
PubMed: 35304599
DOI: 10.1038/s41569-022-00682-0 -
Journal of Neuroengineering and... Oct 2017The following papers by Richard Lieber (Skeletal Muscle as an Actuator), Thomas Roberts (Elastic Mechanisms and Muscle Function), Silvia Blemker (Skeletal Muscle has a... (Review)
Review
The following papers by Richard Lieber (Skeletal Muscle as an Actuator), Thomas Roberts (Elastic Mechanisms and Muscle Function), Silvia Blemker (Skeletal Muscle has a Mind of its Own: a Computational Framework to Model the Complex Process of Muscle Adaptation) and Sabrina Lee (Muscle Properties of Spastic Muscle (Stroke and CP) are summaries of their representative contributions for the session on skeletal muscle mechanics, energetics and plasticity at the 2016 Biomechanics and Neural Control of Movement Conference (BANCOM 2016). Dr. Lieber revisits the topic of sarcomere length as a fundamental property of skeletal muscle contraction. Specifically, problems associated with sarcomere length non-uniformity and the role of sarcomerogenesis in diseases such as cerebral palsy are critically discussed. Dr. Roberts then makes us aware of the (often neglected) role of the passive tissues in muscles and discusses the properties of parallel elasticity and series elasticity, and their role in muscle function. Specifically, he identifies the merits of analyzing muscle deformations in three dimensions (rather than just two), because of the potential decoupling of the parallel elastic element length from the contractile element length, and reviews the associated implications for the architectural gear ratio of skeletal muscle contraction. Dr. Blemker then tackles muscle adaptation using a novel way of looking at adaptive processes and what might drive adaptation. She argues that cells do not have pre-programmed behaviors that are controlled by the nervous system. Rather, the adaptive responses of muscle fibers are determined by sub-cellular signaling pathways that are affected by mechanical and biochemical stimuli; an exciting framework with lots of potential. Finally, Dr. Lee takes on the challenging task of determining human muscle properties in vivo. She identifies the dilemma of how we can demonstrate the effectiveness of a treatment, specifically in cases of muscle spasticity following stroke or in children with cerebral palsy. She then discusses the merits of ultrasound based elastography, and the clinical possibilities this technique might hold. Overall, we are treated to a vast array of basic and clinical problems in skeletal muscle mechanics and physiology, with some solutions, and many suggestions for future research.
Topics: Animals; Elasticity; Humans; Muscle Contraction; Muscle, Skeletal; Sarcomeres
PubMed: 29058612
DOI: 10.1186/s12984-017-0318-y -
Cell Apr 2021Sarcomeres are force-generating and load-bearing devices of muscles. A precise molecular picture of how sarcomeres are built underpins understanding their role in health...
Sarcomeres are force-generating and load-bearing devices of muscles. A precise molecular picture of how sarcomeres are built underpins understanding their role in health and disease. Here, we determine the molecular architecture of native vertebrate skeletal sarcomeres by electron cryo-tomography. Our reconstruction reveals molecular details of the three-dimensional organization and interaction of actin and myosin in the A-band, I-band, and Z-disc and demonstrates that α-actinin cross-links antiparallel actin filaments by forming doublets with 6-nm spacing. Structures of myosin, tropomyosin, and actin at ~10 Å further reveal two conformations of the "double-head" myosin, where the flexible orientation of the lever arm and light chains enable myosin not only to interact with the same actin filament, but also to split between two actin filaments. Our results provide unexpected insights into the fundamental organization of vertebrate skeletal muscle and serve as a strong foundation for future investigations of muscle diseases.
Topics: Actin Cytoskeleton; Actinin; Actomyosin; Animals; Cryoelectron Microscopy; Female; Mice; Mice, Inbred BALB C; Models, Molecular; Muscle, Skeletal; Protein Binding; Sarcomeres; Tropomyosin
PubMed: 33765442
DOI: 10.1016/j.cell.2021.02.047 -
Current Cardiology Reports Jun 2022The lack of adult human cardiomyocyte proliferative capacity impairs cardiac regeneration such as after myocardial injury. The sarcomere, a specialized actin... (Review)
Review
PURPOSE OF REVIEW
The lack of adult human cardiomyocyte proliferative capacity impairs cardiac regeneration such as after myocardial injury. The sarcomere, a specialized actin cytoskeletal structure that is essential for twitch contraction in cardiomyocytes, has been considered a critical factor limiting adult human cardiomyocyte proliferation through incompletely understood mechanisms.
RECENT FINDINGS
This review summarizes known and emerging regulatory mechanisms connecting the human cardiomyocyte sarcomere to cell cycle regulation including structural and signaling mechanisms. Cardiac regeneration could be augmented through targeting the inhibitory effects of the sarcomere on cardiomyocyte proliferation.
Topics: Cell Cycle; Cell Proliferation; Heart; Humans; Myocytes, Cardiac; Regeneration; Sarcomeres; Signal Transduction
PubMed: 35380383
DOI: 10.1007/s11886-022-01682-9 -
Current Cardiology Reports Jun 2023The pace of identifying cardiomyopathy-associated mutations and advances in our understanding of sarcomere function that underlies many cardiomyopathies has been... (Review)
Review
PURPOSE OF REVIEW
The pace of identifying cardiomyopathy-associated mutations and advances in our understanding of sarcomere function that underlies many cardiomyopathies has been remarkable. Here, we aim to synthesize how these advances have led to the promising new treatments that are being developed to treat cardiomyopathies.
RECENT FINDINGS
The genomics era has identified and validated many genetic causes of hypertrophic and dilated cardiomyopathies. Recent advances in our mechanistic understanding of sarcomere pathophysiology include high-resolution molecular models of sarcomere components and the identification of the myosin super-relaxed state. The advances in our understanding of sarcomere function have yielded several therapeutic agents that are now in development and clinical use to correct contractile dysfunction-mediated cardiomyopathy. New genes linked to cardiomyopathy include targets with limited clinical evidence and require additional investigation. Large portions of cardiomyopathy with family history remain genetically undiagnosed and may be due to polygenic disease.
Topics: Humans; Cardiomyopathy, Hypertrophic; Sarcomeres; Cardiomyopathies; Cardiomyopathy, Dilated; Mutation
PubMed: 37060436
DOI: 10.1007/s11886-023-01876-9 -
Circulation Research Jun 2020The adult human heart is an organ with low regenerative potential. Heart failure following acute myocardial infarction is a leading cause of death due to the inability...
RATIONALE
The adult human heart is an organ with low regenerative potential. Heart failure following acute myocardial infarction is a leading cause of death due to the inability of cardiomyocytes to proliferate and replenish lost cardiac muscle. While the zebrafish has emerged as a powerful model to study endogenous cardiac regeneration, the molecular mechanisms by which cardiomyocytes respond to damage by disassembling sarcomeres, proliferating, and repopulating the injured area remain unclear. Furthermore, we are far from understanding the regulation of the chromatin landscape and epigenetic barriers that must be overcome for cardiac regeneration to occur.
OBJECTIVE
To identify transcription factor regulators of the chromatin landscape, which promote cardiomyocyte regeneration in zebrafish, and investigate their function.
METHODS AND RESULTS
Using the Assay for Transposase-Accessible Chromatin coupled to high-throughput sequencing (ATAC-Seq), we first find that the regenerating cardiomyocyte chromatin accessibility landscape undergoes extensive changes following cryoinjury, and that activator protein-1 (AP-1) binding sites are the most highly enriched motifs in regions that gain accessibility during cardiac regeneration. Furthermore, using bioinformatic and gene expression analyses, we find that the AP-1 response in regenerating adult zebrafish cardiomyocytes is largely different from the response in adult mammalian cardiomyocytes. Using a cardiomyocyte-specific dominant negative approach, we show that blocking AP-1 function leads to defects in cardiomyocyte proliferation as well as decreased chromatin accessibility at the and loci, which regulate sarcomere disassembly and cardiomyocyte protrusion into the injured area, respectively. We further show that overexpression of the family members and can promote changes in mammalian cardiomyocyte behavior in vitro.
CONCLUSIONS
AP-1 transcription factors play an essential role in the cardiomyocyte response to injury by regulating chromatin accessibility changes, thereby allowing the activation of gene expression programs that promote cardiomyocyte dedifferentiation, proliferation, and protrusion into the injured area.
Topics: Animals; Cells, Cultured; Chromatin; Myocytes, Cardiac; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Regeneration; Sarcomeres; Transcription Factor AP-1; Zebrafish; Zebrafish Proteins
PubMed: 32312172
DOI: 10.1161/CIRCRESAHA.119.316167 -
European Journal of Heart Failure Sep 2014Although genetic testing has been recommended in patients with hypertrophic cardiomyopathy (HCM) in current clinical practice, its utility in prognostic prediction...
AIMS
Although genetic testing has been recommended in patients with hypertrophic cardiomyopathy (HCM) in current clinical practice, its utility in prognostic prediction remains to be ascertained. We assessed the dosage effect of rare variants in sarcomere genes on the long-term outcomes of HCM.
METHODS AND RESULTS
A total of 529 unrelated HCM patients were prospectively recruited and followed for 4.7 ± 3.2 years. Eight sarcomere genes were screened with targeted resequencing and identified variants were validated through Sanger sequencing. After polymorphisms and likely neutral rare variants were excluded, the patients were segregated into three groups based on the dosage of rare variants: no rare variant, a single rare variant, and multiple rare variants. Multiple rare variants were identified in 7.2% (38/529) of the study patients. Patients with multiple rare variants were younger at diagnosis, and had greater maximum LV wall thicknesses and larger left atria. The risk for cardiovascular death in patients with multiple rare variants was higher than in those without rare variants (P =10⁻⁵) or in those with a single rare variant (P = 2 × 10⁻⁵). Multivariable analysis revealed that multiple rare variants were a risk factor for cardiovascular death [hazard ratio (HR) 3.74, 95% confidence interval (CI) 1.84-7.58, P = 0.0003], as well as sudden cardiac death (HR 3.57, 95% CI 1.23-10.35, P = 0.019) and heart failure-related death (HR 4.62, 95% CI 1.67-12.76, P = 0.003).
CONCLUSIONS
The presence of multiple rare variants in sarcomere genes is a risk factor for malignant outcomes in HCM, and may be appropriate to consider as a criterion in the risk stratification of HCM patients.
Topics: Adult; Cardiomyopathy, Hypertrophic; China; DNA; Female; Follow-Up Studies; Gene Frequency; Genetic Testing; Genetic Variation; Genotype; Humans; Male; Middle Aged; Mutation; Prospective Studies; Risk Factors; Sarcomeres; Survival Rate; Time Factors
PubMed: 25132132
DOI: 10.1002/ejhf.144 -
The Journal of Clinical Investigation Feb 2022A sarcomere is the contractile unit of the myofibril in striated muscles such as cardiac and skeletal muscles. The assembly of sarcomeres depends on multiple molecules...
A sarcomere is the contractile unit of the myofibril in striated muscles such as cardiac and skeletal muscles. The assembly of sarcomeres depends on multiple molecules that serve as raw materials and participate in the assembly process. However, the mechanism of this critical assembly process remains largely unknown. Here, we found that the cell fate determinant Numb and its homolog Numblike regulated sarcomere assembly and maintenance in striated muscles. We discovered that Numb and Numblike are sarcomeric molecules that were gradually confined to the Z-disc during striated muscle development. Conditional knockout of Numb and Numblike severely compromised sarcomere assembly and its integrity and thus caused organelle dysfunction. Notably, we identified that Numb and Numblike served as sarcomeric α-Actin-binding proteins (ABPs) and shared a conserved domain that can bind to the barbed end of sarcomeric α-Actin. In vitro fluorometric α-Actin polymerization assay showed that Numb and Numblike also played a role in the sarcomeric α-Actin polymerization process. Last, we demonstrate that Numb and Numblike regulate sarcomeric α-Actinin-dependent (ACTN-dependent) Z-disc consolidation in the sarcomere assembly and maintenance. In summary, our studies show that Numb and its homolog Numblike regulate sarcomere assembly and maintenance in striated muscles, and demonstrate a molecular mechanism by which Numb/Numblike, sarcomeric α-Actin, and ACTN cooperate to control thin filament formation and Z-disc consolidation.
Topics: Actin Cytoskeleton; Actins; Animals; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Mice, Transgenic; Muscle Development; Nerve Tissue Proteins; Sarcomeres
PubMed: 35104799
DOI: 10.1172/JCI139420 -
Circulation Research Jul 2023Increasing cardiomyocyte contraction during myocardial stretch serves as the basis for the Frank-Starling mechanism in the heart. However, it remains unclear how this...
BACKGROUND
Increasing cardiomyocyte contraction during myocardial stretch serves as the basis for the Frank-Starling mechanism in the heart. However, it remains unclear how this phenomenon occurs regionally within cardiomyocytes, at the level of individual sarcomeres. We investigated sarcomere contractile synchrony and how intersarcomere dynamics contribute to increasing contractility during cell lengthening.
METHODS
Sarcomere strain and Ca were simultaneously recorded in isolated left ventricular cardiomyocytes during 1 Hz field stimulation at 37 °C, at resting length and following stepwise stretch.
RESULTS
We observed that in unstretched rat cardiomyocytes, differential sarcomere deformation occurred during each beat. Specifically, while most sarcomeres shortened during the stimulus, ≈10% to 20% of sarcomeres were stretched or remained stationary. This nonuniform strain was not traced to regional Ca disparities but rather shorter resting lengths and lower force production in systolically stretched sarcomeres. Lengthening of the cell recruited additional shortening sarcomeres, which increased contractile efficiency as less negative, wasted work was performed by stretched sarcomeres. Given the known role of titin in setting sarcomere dimensions, we next hypothesized that modulating titin expression would alter intersarcomere dynamics. Indeed, in cardiomyocytes from mice with titin haploinsufficiency, we observed greater variability in resting sarcomere length, lower recruitment of shortening sarcomeres, and impaired work performance during cell lengthening.
CONCLUSIONS
Graded sarcomere recruitment directs cardiomyocyte work performance, and harmonization of sarcomere strain increases contractility during cell stretch. By setting sarcomere dimensions, titin controls sarcomere recruitment, and its lowered expression in haploinsufficiency mutations impairs cardiomyocyte contractility.
Topics: Rats; Mice; Animals; Sarcomeres; Connectin; Myocytes, Cardiac; Myocardial Contraction; Myocardium
PubMed: 37401464
DOI: 10.1161/CIRCRESAHA.123.322588