-
Journal of Molecular and Cellular... Nov 2020The sarcomere is the basic contractile unit of striated muscle and is a highly ordered protein complex with the actin and myosin filaments at its core. Assembling the... (Review)
Review
The sarcomere is the basic contractile unit of striated muscle and is a highly ordered protein complex with the actin and myosin filaments at its core. Assembling the sarcomere constituents into this organized structure in development, and with muscle growth as new sarcomeres are built, is a complex process coordinated by numerous factors. Once assembled, the sarcomere requires constant maintenance as its continuous contraction is accompanied by elevated mechanical, thermal, and oxidative stress, which predispose proteins to misfolding and toxic aggregation. To prevent protein misfolding and maintain sarcomere integrity, the sarcomere is monitored by an assortment of protein quality control (PQC) mechanisms. The need for effective PQC is heightened in cardiomyocytes which are terminally differentiated and must survive for many years while preserving optimal mechanical output. To prevent toxic protein aggregation, molecular chaperones stabilize denatured sarcomere proteins and promote their refolding. However, when old and misfolded proteins cannot be salvaged by chaperones, they must be recycled via degradation pathways: the calpain and ubiquitin-proteasome systems, which operate under basal conditions, and the stress-responsive autophagy-lysosome pathway. Mutations to and deficiency of the molecular chaperones and associated factors charged with sarcomere maintenance commonly lead to sarcomere structural disarray and the progression of heart disease, highlighting the necessity of effective sarcomere PQC for maintaining cardiac function. This review focuses on the dynamic regulation of assembly and turnover at the sarcomere with an emphasis on the chaperones involved in these processes and describes the alterations to chaperones - through mutations and deficient expression - implicated in disease progression to heart failure.
Topics: Animals; Autophagy; Humans; Lysosomes; Models, Biological; Myocardium; Myofibrils; Sarcomeres
PubMed: 32920010
DOI: 10.1016/j.yjmcc.2020.08.018 -
The Journal of General Physiology Mar 2021The March 2021 issue of is a collection of peer-reviewed articles focused on the function and dynamic regulation of contractile systems in muscle and non-muscle cells.
The March 2021 issue of is a collection of peer-reviewed articles focused on the function and dynamic regulation of contractile systems in muscle and non-muscle cells.
Topics: Muscle Proteins; Myofibrils
PubMed: 33620422
DOI: 10.1085/jgp.202112880 -
Comprehensive Physiology Mar 2018Sarcomeres consist of highly ordered arrays of thick myosin and thin actin filaments along with accessory proteins. Thick filaments occupy the center of sarcomeres where... (Review)
Review
Sarcomeres consist of highly ordered arrays of thick myosin and thin actin filaments along with accessory proteins. Thick filaments occupy the center of sarcomeres where they partially overlap with thin filaments. The sliding of thick filaments past thin filaments is a highly regulated process that occurs in an ATP-dependent manner driving muscle contraction. In addition to myosin that makes up the backbone of the thick filament, four other proteins which are intimately bound to the thick filament, myosin binding protein-C, titin, myomesin, and obscurin play important structural and regulatory roles. Consistent with this, mutations in the respective genes have been associated with idiopathic and congenital forms of skeletal and cardiac myopathies. In this review, we aim to summarize our current knowledge on the molecular structure, subcellular localization, interacting partners, function, modulation via posttranslational modifications, and disease involvement of these five major proteins that comprise the thick filament of striated muscle cells. © 2018 American Physiological Society. Compr Physiol 8:631-709, 2018.
Topics: Animals; Humans; Muscle Contraction; Muscle Proteins; Muscle, Skeletal; Muscular Diseases; Mutation; Myofibrils; Myosins; Sarcomeres
PubMed: 29687901
DOI: 10.1002/cphy.c170023 -
Science (New York, N.Y.) Feb 2022In skeletal muscle, nebulin stabilizes and regulates the length of thin filaments, but the underlying mechanism remains nebulous. In this work, we used cryo-electron...
In skeletal muscle, nebulin stabilizes and regulates the length of thin filaments, but the underlying mechanism remains nebulous. In this work, we used cryo-electron tomography and subtomogram averaging to reveal structures of native nebulin bound to thin filaments within intact sarcomeres. This in situ reconstruction provided high-resolution details of the interaction between nebulin and actin, demonstrating the stabilizing role of nebulin. Myosin bound to the thin filaments exhibited different conformations of the neck domain, highlighting its inherent structural variability in muscle. Unexpectedly, nebulin did not interact with myosin or tropomyosin, but it did interact with a troponin T linker through two potential binding motifs on nebulin, explaining its regulatory role. Our structures support the role of nebulin as a thin filament "molecular ruler" and provide a molecular basis for studying nemaline myopathies.
Topics: Actin Cytoskeleton; Actins; Animals; Electron Microscope Tomography; Humans; Mice; Mice, Inbred BALB C; Models, Molecular; Muscle Proteins; Mutation; Myocardium; Myofibrils; Myopathies, Nemaline; Myosins; Protein Conformation; Protein Structure, Secondary; Psoas Muscles; Sarcomeres
PubMed: 35175800
DOI: 10.1126/science.abn1934 -
Animal Science Journal = Nihon Chikusan... Jul 2019Skeletal muscle consists of bundles of myofibers containing millions of myofibrils, each of which is formed of longitudinally aligned sarcomere structures. Sarcomeres... (Review)
Review
Skeletal muscle consists of bundles of myofibers containing millions of myofibrils, each of which is formed of longitudinally aligned sarcomere structures. Sarcomeres are the minimum contractile unit, which mainly consists of four components: Z-bands, thin filaments, thick filaments, and connectin/titin. The size and shape of the sarcomere component is strictly controlled. Surprisingly, skeletal muscle cells not only synthesize a series of myofibrillar proteins but also regulate the assembly of those proteins into the sarcomere structures. However, authentic sarcomere structures cannot be reconstituted by combining purified myofibrillar proteins in vitro, therefore there must be an elaborate mechanism ensuring the correct formation of myofibril structure in skeletal muscle cells. This review discusses the role of myosin, a main component of the thick filament, in thick filament formation and the dynamics of myosin in skeletal muscle cells. Changes in the number of myofibrils in myofibers can cause muscle hypertrophy or atrophy. Therefore, it is important to understand the fundamental mechanisms by which myofibers control myofibril formation at the molecular level to develop approaches that effectively enhance muscle growth in animals.
Topics: Animals; Atrophy; Cytoskeleton; Hypertrophy; Muscle, Skeletal; Myofibrils; Myosins; Sarcomeres
PubMed: 31134719
DOI: 10.1111/asj.13226 -
Circulation Research Jun 2020
Topics: Estrogens; Heart; Myofibrils
PubMed: 32496915
DOI: 10.1161/CIRCRESAHA.120.317052 -
Circulation Research Jan 2024A healthy heart is able to modify its function and increase relaxation through post-translational modifications of myofilament proteins. While there are known examples...
BACKGROUND
A healthy heart is able to modify its function and increase relaxation through post-translational modifications of myofilament proteins. While there are known examples of serine/threonine kinases directly phosphorylating myofilament proteins to modify heart function, the roles of tyrosine (Y) phosphorylation to directly modify heart function have not been demonstrated. The myofilament protein TnI (troponin I) is the inhibitory subunit of the troponin complex and is a key regulator of cardiac contraction and relaxation. We previously demonstrated that TnI-Y26 phosphorylation decreases calcium-sensitive force development and accelerates calcium dissociation, suggesting a novel role for tyrosine kinase-mediated TnI-Y26 phosphorylation to regulate cardiac relaxation. Therefore, we hypothesize that increasing TnI-Y26 phosphorylation will increase cardiac relaxation in vivo and be beneficial during pathological diastolic dysfunction.
METHODS
The signaling pathway involved in TnI-Y26 phosphorylation was predicted in silico and validated by tyrosine kinase activation and inhibition in primary adult murine cardiomyocytes. To investigate how TnI-Y26 phosphorylation affects cardiac muscle, structure, and function in vivo, we developed a novel TnI-Y26 phosphorylation-mimetic mouse that was subjected to echocardiography, pressure-volume loop hemodynamics, and myofibril mechanical studies. TnI-Y26 phosphorylation-mimetic mice were further subjected to the nephrectomy/DOCA (deoxycorticosterone acetate) model of diastolic dysfunction to investigate the effects of increased TnI-Y26 phosphorylation in disease.
RESULTS
Src tyrosine kinase is sufficient to phosphorylate TnI-Y26 in cardiomyocytes. TnI-Y26 phosphorylation accelerates in vivo relaxation without detrimental structural or systolic impairment. In a mouse model of diastolic dysfunction, TnI-Y26 phosphorylation is beneficial and protects against the development of disease.
CONCLUSIONS
We have demonstrated that tyrosine kinase phosphorylation of TnI is a novel mechanism to directly and beneficially accelerate myocardial relaxation in vivo.
Topics: Mice; Animals; Phosphorylation; Troponin I; Calcium; Protein Processing, Post-Translational; Myocardial Contraction; Myofibrils; Protein-Tyrosine Kinases; Tyrosine
PubMed: 38095088
DOI: 10.1161/CIRCRESAHA.123.323132 -
The Journal of Physiology Jun 2017The major goal of this focused review is to highlight some of the recent advances and remaining open questions about how a mutation in a myofilament protein leads to an... (Review)
Review
The major goal of this focused review is to highlight some of the recent advances and remaining open questions about how a mutation in a myofilament protein leads to an increased risk for sudden cardiac death (SCD). The link between myofilaments and SCD has been known for over 25 years, but identifying mutation carriers at risk for SCD is still a challenge and currently the only effective prevention is implantation of a defibrillator (ICD). In addition to recognized risk factors, other contributing factors need to be considered and assessed, e.g. 'microvascular dysfunction', to calibrate individual risk more accurately. Similarly, improving our understanding about the underlying mechanisms of SCD in patients with sarcomeric mutations will also allow us to design new and less invasive treatment options that will minimize risk and hopefully make implantation of an ICD unnecessary.
Topics: Animals; Death, Sudden, Cardiac; Defibrillators, Implantable; Humans; Myofibrils; Risk Factors
PubMed: 28205229
DOI: 10.1113/JP273047 -
Journal of Molecular and Cellular... Aug 2018
Topics: Heart; Humans; Myocardial Contraction; Myofibrils; Sarcomeres
PubMed: 29908919
DOI: 10.1016/j.yjmcc.2018.06.003 -
The Journal of General Physiology Feb 2022Myofilaments and their associated proteins, which together constitute the sarcomeres, provide the molecular-level basis for contractile function in all muscle types. In... (Review)
Review
Myofilaments and their associated proteins, which together constitute the sarcomeres, provide the molecular-level basis for contractile function in all muscle types. In intact muscle, sarcomere-level contraction is strongly coupled to other cellular subsystems, in particular the sarcolemmal membrane. Skinned muscle preparations (where the sarcolemma has been removed or permeabilized) are an experimental system designed to probe contractile mechanisms independently of the sarcolemma. Over the last few decades, experiments performed using permeabilized preparations have been invaluable for clarifying the understanding of contractile mechanisms in both skeletal and cardiac muscle. Today, the technique is increasingly harnessed for preclinical and/or pharmacological studies that seek to understand how interventions will impact intact muscle contraction. In this context, intrinsic functional and structural differences between skinned and intact muscle pose a major interpretational challenge. This review first surveys measurements that highlight these differences in terms of the sarcomere structure, passive and active tension generation, and calcium dependence. We then highlight the main practical challenges and caveats faced by experimentalists seeking to emulate the physiological conditions of intact muscle. Gaining an awareness of these complexities is essential for putting experiments in due perspective.
Topics: Calcium; Muscle Contraction; Myocardial Contraction; Myocardium; Myofibrils; Sarcomeres
PubMed: 35045156
DOI: 10.1085/jgp.202112990