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Developmental Dynamics : An Official... Jan 2021Muscle myofibrils and sarcomeres present exceptional examples of highly ordered cytoskeletal filament arrays, whose distinct spatial organization is an essential aspect...
BACKGROUND
Muscle myofibrils and sarcomeres present exceptional examples of highly ordered cytoskeletal filament arrays, whose distinct spatial organization is an essential aspect of muscle cell functionality. We utilized ultra-structural analysis to investigate the assembly of myofibrils and sarcomeres within developing myotubes of the indirect flight musculature of Drosophila.
RESULTS
A temporal sequence composed of three major processes was identified: subdivision of the unorganized cytoplasm of nascent, multi-nucleated myotubes into distinct organelle-rich and filament-rich domains; initial organization of the filament-rich domains into myofibrils harboring nascent sarcomeric units; and finally, maturation of the highly-ordered pattern of sarcomeric thick (myosin-based) and thin (microfilament-based) filament arrays in parallel to myofibril radial growth. Significantly, organized microtubule arrays were present throughout these stages and exhibited dynamic changes in their spatial patterns consistent with instructive roles. Genetic manipulations confirm these notions, and imply specific and critical guidance activities of the microtubule-based cytoskeleton, as well as structural interdependence between the myosin- and actin-based filament arrays.
CONCLUSIONS
Our observations highlight a surprisingly significant, behind-the-scenes role for microtubules in establishment of myofibril and sarcomere spatial patterns and size, and provide a detailed account of the interplay between major cytoskeletal elements in generating these essential contractile myogenic units.
Topics: Animals; Cytoskeleton; Drosophila; Muscle Development; Pupa; Sarcomeres
PubMed: 32725855
DOI: 10.1002/dvdy.227 -
Trends in Molecular Medicine Sep 2019Hypertrophic cardiomyopathy (HCM) is a prevalent and complex cardiovascular disease where cardiac dysfunction often associates with mutations in sarcomeric genes.... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a prevalent and complex cardiovascular disease where cardiac dysfunction often associates with mutations in sarcomeric genes. Various models based on tissue explants, isolated cardiomyocytes, skinned myofibrils, and purified actin/myosin preparations have uncovered disease hallmarks, enabling the development of putative therapeutics, with some reaching clinical trials. Newly developed human pluripotent stem cell (hPSC)-based models could be complementary by overcoming some of the inconsistencies of earlier systems, whilst challenging and/or clarifying previous findings. In this article we compare recent progress in unveiling multiple HCM mechanisms in different models, highlighting similarities and discrepancies. We explore how insight is facilitating the design of new HCM therapeutics, including those that regulate metabolism, contraction and heart rhythm, providing a future perspective for treatment of HCM.
Topics: Animals; Biomarkers; CRISPR-Cas Systems; Cardiomyopathy, Hypertrophic; Disease Models, Animal; Disease Susceptibility; Gene Editing; Humans; Models, Biological; Molecular Targeted Therapy; Muscle Contraction; Myocardium; Myocytes, Cardiac; Pluripotent Stem Cells; Sarcomeres
PubMed: 31324451
DOI: 10.1016/j.molmed.2019.06.005 -
International Journal of Molecular... Apr 2020Filamin C (FLNC) is one of three filamin proteins (Filamin A (FLNA), Filamin B (FLNB), and FLNC) that cross-link actin filaments and interact with numerous binding... (Review)
Review
Filamin C (FLNC) is one of three filamin proteins (Filamin A (FLNA), Filamin B (FLNB), and FLNC) that cross-link actin filaments and interact with numerous binding partners. FLNC consists of a N-terminal actin-binding domain followed by 24 immunoglobulin-like repeats with two intervening calpain-sensitive hinges separating R15 and R16 (hinge 1) and R23 and R24 (hinge-2). The FLNC subunit is dimerized through R24 and calpain cleaves off the dimerization domain to regulate mobility of the FLNC subunit. FLNC is localized in the Z-disc due to the unique insertion of 82 amino acid residues in repeat 20 and necessary for normal Z-disc formation that connect sarcomeres. Since phosphorylation of FLNC by PKC diminishes the calpain sensitivity, assembly, and disassembly of the Z-disc may be regulated by phosphorylation of FLNC. Mutations of FLNC result in cardiomyopathy and muscle weakness. Although this review will focus on the current understanding of FLNC structure and functions in muscle, we will also discuss other filamins because they share high sequence similarity and are better characterized. We will also discuss a possible role of FLNC as a mechanosensor during muscle contraction.
Topics: Animals; Carrier Proteins; Filamins; Humans; Models, Molecular; Molecular Structure; Muscle Cells; Muscular Diseases; Mutation; Protein Binding; Protein Conformation; Protein Processing, Post-Translational; Sarcomeres; Structure-Activity Relationship
PubMed: 32295012
DOI: 10.3390/ijms21082696 -
Journal of Molecular and Cellular... Feb 2016
Topics: Animals; Biomechanical Phenomena; Calcium; Elasticity; Heart Ventricles; Humans; Myocardial Contraction; Myocardium; Sarcomeres; Stress, Mechanical; Stroke Volume
PubMed: 26678623
DOI: 10.1016/j.yjmcc.2015.12.006 -
Nature Communications Oct 2022Sustained muscle contraction occurs through interactions between actin and myosin filaments within sarcomeres and requires a constant supply of adenosine triphosphate...
Sustained muscle contraction occurs through interactions between actin and myosin filaments within sarcomeres and requires a constant supply of adenosine triphosphate (ATP) from nearby mitochondria. However, it remains unclear how different physical configurations between sarcomeres and mitochondria alter the energetic support for contractile function. Here, we show that sarcomere cross-sectional area (CSA) varies along its length in a cell type-dependent manner where the reduction in Z-disk CSA relative to the sarcomere center is closely coordinated with mitochondrial network configuration in flies, mice, and humans. Further, we find myosin filaments near the sarcomere periphery are curved relative to interior filaments with greater curvature for filaments near mitochondria compared to sarcoplasmic reticulum. Finally, we demonstrate variable myosin filament lattice spacing between filament ends and filament centers in a cell type-dependent manner. These data suggest both sarcomere structure and myofilament interactions are influenced by the location and orientation of mitochondria within muscle cells.
Topics: Actins; Adenosine Triphosphate; Animals; Humans; Mice; Mitochondria; Muscle Contraction; Muscle, Striated; Myosins; Sarcomeres
PubMed: 36229433
DOI: 10.1038/s41467-022-33678-y -
Journal of Molecular and Cellular... Apr 2015Driven by rapidly evolving technologies in next-generation sequencing, alternative splicing has emerged as a crucial layer in gene expression, greatly expanding protein... (Review)
Review
Driven by rapidly evolving technologies in next-generation sequencing, alternative splicing has emerged as a crucial layer in gene expression, greatly expanding protein diversity and governing complex biological processes in the cardiomyocyte. At the core of cardiac contraction, the physical properties of the sarcomere are carefully orchestrated through alternative splicing to fit the varying demands on the heart. By the recent discovery of RBM20 and RBM24, two major heart and skeletal muscle-restricted splicing factors, it became evident that alternative splicing events in the heart occur in regulated networks rather than in isolated events. Analysis of knockout mice of these splice factors has shed light on the importance of these fundamental processes in the heart. In this review, we discuss recent advances in our understanding of the role and regulation of alternative splicing in the developing and diseased heart, specifically within the sarcomere. Through various examples (titin, myomesin, troponin T, tropomyosin and LDB3) we illustrate how alternative splicing regulates the functional properties of the sarcomere. Finally, we evaluate opportunities and obstacles to modulate alternative splicing in therapeutic approaches for cardiac disease.
Topics: Adaptor Proteins, Signal Transducing; Alternative Splicing; Animals; Connectin; Gene Expression Regulation, Developmental; Heart Diseases; Humans; LIM Domain Proteins; Mice; Myocardial Contraction; Myocardium; Protein Kinases; RNA-Binding Proteins; Sarcomeres; Signal Transduction; Tropomyosin; Troponin T
PubMed: 25683494
DOI: 10.1016/j.yjmcc.2015.02.008 -
Journal of Applied Physiology... Aug 2023During natural aging, skeletal muscle experiences impairments in mechanical performance due, in part, to changes in muscle architecture and size, notably with a loss of... (Review)
Review
During natural aging, skeletal muscle experiences impairments in mechanical performance due, in part, to changes in muscle architecture and size, notably with a loss of muscle cross-sectional area (CSA). Another important factor that has received less attention is the shortening of fascicle length (FL), potentially reflective of a decrease in serial sarcomere number (SSN). Interventions that promote the growth of new serial sarcomeres, such as chronic stretching and eccentric-biased resistance training, have been suggested as potential ways to mitigate age-related impairments in muscle function. Although current research suggests it is possible to stimulate serial sarcomerogenesis in muscle in old age, the magnitude of sarcomerogenesis may be less than in young muscle. This blunted effect may be partly due to age-related impairments in the pathways regulating mechanotransduction, muscle gene expression, and protein synthesis, as some have been implicated in SSN adaptation. The purpose of this review was to investigate the impact of aging on the ability for serial sarcomerogenesis and elucidate the molecular pathways that may limit serial sarcomerogenesis in old age. Age-related changes in mechanistic target of rapamycin (mTOR), insulin-like growth factor 1 (IGF-1), myostatin, and serum response factor signaling, muscle ring finger protein (MuRFs), and satellite cells may hinder serial sarcomerogenesis. In addition, our current understanding of SSN in older humans is limited by assumptions based on ultrasound-derived fascicle length. Future research should explore the effects of age-related changes in the identified pathways on the ability to stimulate serial sarcomerogenesis, and better estimate SSN adaptations to gain a deeper understanding of the adaptability of muscle in old age.
Topics: Humans; Aged; Sarcomeres; Mechanotransduction, Cellular; Muscle, Skeletal; Aging; Musculoskeletal Physiological Phenomena
PubMed: 37410905
DOI: 10.1152/japplphysiol.00205.2023 -
Journal of Genetics and Genomics = Yi... Mar 2021Skeletal and cardiac muscles are striated myofibers that contain highly organized sarcomeres for muscle contraction. Recent studies revealed that Smyd1, a lysine...
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, smyd1a and smyd1b, in craniofacial and cardiac muscles of zebrafish embryos. Our data show that loss of smyd1a (smyd1a) or smyd1b (smyd1b) has no visible effects on myogenic commitment and expression of myod and myosin heavy-chain mRNA transcripts in craniofacial muscles. However, myosin heavy-chain protein accumulation and sarcomere organization are dramatically reduced in smyd1b single mutant, and almost completely diminish in smyd1a; smyd1b double mutant, but not in smyd1a mutant. Similar defects are also observed in cardiac muscles of smyd1b mutant. Defective craniofacial and cardiac muscle formation is associated with an upregulation of hsp90α1 and unc45b mRNA expression in smyd1b and smyd1a; smyd1b 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.
Topics: Animals; Myocardium; Myosins; Sarcomeres; Zebrafish
PubMed: 33958316
DOI: 10.1016/j.jgg.2021.03.004 -
The Journal of Experimental Biology Jan 2016During the past century, physiologists have made steady progress in elucidating the molecular mechanisms of muscle contraction. However, this progress has so far failed... (Review)
Review
During the past century, physiologists have made steady progress in elucidating the molecular mechanisms of muscle contraction. However, this progress has so far failed to definitively explain the high force and low energy cost of eccentric muscle contraction. Hypotheses that have been proposed to explain increased muscle force during active stretch include cross-bridge mechanisms, sarcomere and half-sarcomere length non-uniformity, and engagement of a structural element upon muscle activation. The available evidence suggests that force enhancement results from an interaction between an elastic element in muscle sarcomeres, which is engaged upon activation, and the cross-bridges, which interact with the elastic elements to regulate their length and stiffness. Similarities between titin-based residual force enhancement in vertebrate muscle and twitchin-based 'catch' in invertebrate muscle suggest evolutionary homology. The winding filament hypothesis suggests plausible molecular mechanisms for effects of both Ca(2+) influx and cross-bridge cycling on titin in active muscle. This hypothesis proposes that the N2A region of titin binds to actin upon Ca(2+) influx, and that the PEVK region of titin winds on the thin filaments during force development because the cross-bridges not only translate but also rotate the thin filaments. Simulations demonstrate that a muscle model based on the winding filament hypothesis can predict residual force enhancement on the descending limb of the length-tension curve in muscles during eccentric contraction. A kinematic model of titin winding based on sarcomere geometry makes testable predictions about titin isoforms in different muscles. Ongoing research is aimed at testing these predictions and elucidating the biochemistry of the underlying protein interactions.
Topics: Animals; Biomechanical Phenomena; Connectin; Energy Metabolism; Humans; Models, Biological; Muscle Contraction; Sarcomeres
PubMed: 26792330
DOI: 10.1242/jeb.124057 -
Journal of Muscle Research and Cell... Jun 2021Appropriate organization of cytoskeletal components are required for normal distribution and intracellular localization of different ion channels and proteins involved... (Review)
Review
Appropriate organization of cytoskeletal components are required for normal distribution and intracellular localization of different ion channels and proteins involved in calcium homeostasis, signal transduction, and contractile function of striated muscle. Proteins of the contractile system are in direct or indirect connection with the extrasarcomeric cytoskeleton. A number of other molecules which have essential role in regulating stretch-, voltage-, and chemical signal transduction from the surface into the cytoplasm or other intracellular compartments are already well characterized. Sarcomere, the basic contractile unit, is comprised of a precisely organized system of thin (actin), and thick (myosin) filaments. Intermediate filaments connect the sarcomeres and other organelles (mitochondria and nucleus), and are responsible for the cellular integrity. Interacting proteins have a very diverse function in coupling of the intracellular assembly components and regulating the normal physiological function. Despite the more and more intense investigations of a new cytoskeletal protein family, the septins, only limited information is available regarding their expression and role in striated, especially in skeletal muscles. In this review we collected basic and specified knowledge regarding this protein group and emphasize the importance of this emerging field in skeletal muscle biology.
Topics: Cytoskeleton; Muscle, Skeletal; Muscle, Striated; Sarcomeres; Septins
PubMed: 31955380
DOI: 10.1007/s10974-020-09573-8