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Journal of Applied Physiology... Jul 2022Skeletal muscle has the remarkable ability to remodel and adapt, such as the increase in serial sarcomere number (SSN) or fascicle length (FL) observed after... (Review)
Review
Skeletal muscle has the remarkable ability to remodel and adapt, such as the increase in serial sarcomere number (SSN) or fascicle length (FL) observed after overstretching a muscle. This type of remodeling is termed longitudinal muscle fascicle growth, and its impact on biomechanical function has been of interest since the 1960s due to its clinical applications in muscle strain injury, muscle spasticity, and sarcopenia. Despite simplified hypotheses on how longitudinal muscle fascicle growth might influence mechanical function, existing literature presents conflicting results partly due to a breadth of methodologies. The purpose of this review is to outline what is currently known about the influence of longitudinal muscle fascicle growth on mechanical function and suggest future directions to address current knowledge gaps and methodological limitations. Various interventions indicate longitudinal muscle fascicle growth can increase the optimal muscle length for active force, but whether the whole force-length relationship widens has been less investigated. Future research should also explore the ability for longitudinal fascicle growth to broaden the torque-angle relationship's plateau region, and the relation to increased force during shortening. Without a concurrent increase in intramuscular collagen, longitudinal muscle fascicle growth also reduces passive tension at long muscle lengths; further research is required to understand whether this translates to increased joint range of motion. Finally, some evidence suggests longitudinal fascicle growth can increase maximum shortening velocity and peak isotonic power; however, there has yet to be direct assessment of these measures in a neurologically intact model of longitudinal muscle fascicle growth.
Topics: Biomechanical Phenomena; Humans; Muscle Spasticity; Muscle, Skeletal; Range of Motion, Articular; Sarcomeres; Torque
PubMed: 35608202
DOI: 10.1152/japplphysiol.00114.2022 -
American Journal of Cardiovascular... Sep 2022Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease of the cardiomyocyte with a diverse and heterogeneous clinical presentation and course. This... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease of the cardiomyocyte with a diverse and heterogeneous clinical presentation and course. This diversity and heterogeneity have added to the complexity of modeling the pathophysiological pathways that contribute to the disease burden. The development of novel therapeutic approaches targeting precise mechanisms within the underlying biology of HCM provides a tool to model and test these pathways. Here, we integrate the results of clinical observations with mavacamten, an allosteric, selective, and reversible inhibitor of cardiac myosin, the motor unit of the sarcomere, to develop an integrated pathophysiological pathway model of HCM, confirming the key role of excess sarcomeric activity. This model may serve as a foundation to understand the role of HCM pathophysiological pathways in the clinical presentation of the disease, and how a targeted therapeutic intervention capable of normalizing sarcomeric activity and repopulating low-energy utilization states may reduce the impact of these pathways in HCM and potentially related disease states.
Topics: Benzylamines; Cardiomyopathy, Hypertrophic; Humans; Sarcomeres; Uracil
PubMed: 35435607
DOI: 10.1007/s40256-022-00532-x -
Biological Chemistry Nov 2014The giant sarcomeric protein titin has multiple important functions in striated muscle cells. Due to its gigantic size, its central position in the sarcomere and its... (Review)
Review
The giant sarcomeric protein titin has multiple important functions in striated muscle cells. Due to its gigantic size, its central position in the sarcomere and its elastic I-band domains, titin is a scaffold protein that is important for sarcomere assembly, and serves as a molecular spring that defines myofilament distensibility. This review focuses on the emerging role of titin in mechanosensing and hypertrophic signaling, and further highlights recent evidence that links titin to sarcomeric protein turnover.
Topics: Animals; Connectin; Humans; Mechanotransduction, Cellular; Molecular Chaperones; Protein Conformation; Sarcomeres; Signal Transduction
PubMed: 25205716
DOI: 10.1515/hsz-2014-0178 -
Developmental Biology Oct 2022Cell growth and proliferation must be balanced during development to attain a final adult size with the appropriate proportions of internal organs to maximize fitness...
Cell growth and proliferation must be balanced during development to attain a final adult size with the appropriate proportions of internal organs to maximize fitness and reproduction. While multiple signaling pathways coordinate Drosophila development, it is unclear how multi-organ communication within and between tissues converge to regulate systemic growth. One such growth pathway, mediated by insulin-like peptides that bind to and activate the insulin receptor in multiple target tissues, is a primary mediator of organismal size. Here we uncover a signaling role for the NUAK serine/threonine kinase in muscle tissue that impinges upon insulin pathway activity to limit overall body size, including a reduction in the growth of individual organs. In skeletal muscle tissue, manipulation of NUAK or insulin pathway components influences sarcomere number concomitant with modulation of thin and thick filament lengths, possibly by modulating the localization of Lasp, a nebulin repeat protein known to set thin filament length. This mode of sarcomere remodeling does not occur in other mutants that also exhibit smaller muscles, suggesting that a sensing mechanism exists in muscle tissue to regulate sarcomere growth that is independent of tissue size control.
Topics: Actin Cytoskeleton; Animals; Drosophila; Insulins; Muscle, Skeletal; Sarcomeres
PubMed: 35760368
DOI: 10.1016/j.ydbio.2022.06.014 -
Journal of Biomechanics Dec 2021Understanding passive skeletal muscle mechanics is critical in defining structure-function relationships in skeletal muscle and ultimately understanding pathologically... (Review)
Review
Understanding passive skeletal muscle mechanics is critical in defining structure-function relationships in skeletal muscle and ultimately understanding pathologically impaired muscle. In this systematic review, we performed an exhaustive literature search using PRISMA guidelines to quantify passive muscle mechanical properties, summarized the methods used to create these data, and make recommendations to standardize future studies. We screened over 7500 papers and found 80 papers that met the inclusion criteria. These papers reported passive muscle mechanics from single muscle fiber to whole muscle across 16 species and 54 distinct muscles. We found a wide range of methodological differences in sample selection, preparation, testing, and analysis. The systematic review revealed that passive muscle mechanics is species and scale dependent-specifically within mammals, the passive mechanics increases non-linearly with scale. However, a detailed understanding of passive mechanics is still unclear because the varied methodologies impede comparisons across studies, scales, species, and muscles. Therefore, we recommend the following: smaller scales may be maintained within storage solution prior to testing, when samples are tested statically use 2-3 min of relaxation time, stress normalization at the whole muscle level be to physiologic cross-sectional area, strain normalization be to sarcomere length when possible, and an exponential equation be used to fit the data. Additional studies using these recommendations will allow exploration of the multiscale relationship of passive force within and across species to provide the fundamental knowledge needed to improve our understanding of passive muscle mechanics.
Topics: Animals; Muscle Fibers, Skeletal; Muscle, Skeletal; Sarcomeres
PubMed: 34736082
DOI: 10.1016/j.jbiomech.2021.110839 -
Quarterly Reviews of Biophysics Jan 2023The cardiac sarcomere is a cellular structure in the heart that enables muscle cells to contract. Dozens of proteins belong to the cardiac sarcomere, which work in... (Review)
Review
The cardiac sarcomere is a cellular structure in the heart that enables muscle cells to contract. Dozens of proteins belong to the cardiac sarcomere, which work in tandem to generate force and adapt to demands on cardiac output. Intriguingly, the majority of these proteins have significant intrinsic disorder that contributes to their functions, yet the biophysics of these intrinsically disordered regions (IDRs) have been characterized in limited detail. In this review, we first enumerate these myofilament-associated proteins with intrinsic disorder (MAPIDs) and recent biophysical studies to characterize their IDRs. We secondly summarize the biophysics governing IDR properties and the state-of-the-art in computational tools toward MAPID identification and characterization of their conformation ensembles. We conclude with an overview of future computational approaches toward broadening the understanding of intrinsic disorder in the cardiac sarcomere.
Topics: Myofibrils; Actin Cytoskeleton; Sarcomeres; Computer Simulation; Molecular Conformation
PubMed: 36628457
DOI: 10.1017/S003358352300001X -
Biochimica Et Biophysica Acta Jul 2016Human heart failure due to myocardial infarction is a major health concern. The paucity of organs for transplantation limits curative approaches for the diseased and... (Review)
Review
Human heart failure due to myocardial infarction is a major health concern. The paucity of organs for transplantation limits curative approaches for the diseased and failing adult heart. Human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs) have the potential to provide a long-term, viable, regenerative-medicine alternative. Significant progress has been made with regard to efficient cardiac myocyte generation from hiPSCs. However, directing hiPSC-CMs to acquire the physiological structure, gene expression profile and function akin to mature cardiac tissue remains a major obstacle. Thus, hiPSC-CMs have several hurdles to overcome before they find their way into translational medicine. In this review, we address the progress that has been made, the void in knowledge and the challenges that remain. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
Topics: Calcium Signaling; Cardiovascular Agents; Cell Differentiation; Cell Lineage; Cells, Cultured; Drug Discovery; Gene Expression Regulation, Developmental; Genetic Markers; Genotype; Heart Diseases; Humans; Induced Pluripotent Stem Cells; Mutation; Myocardial Contraction; Myocytes, Cardiac; Phenotype; Recovery of Function; Regeneration; Regenerative Medicine; Sarcomeres; Stem Cell Transplantation; Tissue Engineering
PubMed: 26578113
DOI: 10.1016/j.bbamcr.2015.11.005 -
Journal of the American Heart... Dec 2019Background A genetic cause can be identified in 30% of noncompaction cardiomyopathy patients (NCCM) with clinical features ranging from asymptomatic cardiomyopathy to... (Comparative Study)
Comparative Study
Background A genetic cause can be identified in 30% of noncompaction cardiomyopathy patients (NCCM) with clinical features ranging from asymptomatic cardiomyopathy to heart failure with major adverse cardiac events (MACE). Methods and Results To investigate genotype-phenotype correlations, the genotypes and clinical features of genetic NCCM patients were collected from the literature. We compared age at diagnosis, cardiac features and risk for MACE according to mode of inheritance and molecular effects for defects in the most common sarcomere genes and NCCM subtypes. Geno- and phenotypes of 561 NCCM patients from 172 studies showed increased risk in children for congenital heart defects (<0.001) and MACE (<0.001). In adult NCCM patients the main causes were single missense mutations in sarcomere genes. Children more frequently had an X-linked or mitochondrial inherited defect (=0.001) or chromosomal anomalies (<0.001). was involved in 48% of the sarcomere gene mutations. and mutations had lower risk for MACE than and (=0.001). The NCCM/dilated cardiomyopathy cardiac phenotype was the most frequent subtype (56%; =0.022) and was associated with an increased risk for MACE and high risk for left ventricular systolic dysfunction (<0.001). In multivariate binary logistic regression analysis , arrhythmia -, non-sarcomere non-arrhythmia cardiomyopathy-and X-linked genes were genetic predictors for MACE. Conclusions Sarcomere gene mutations were the most common cause in adult patients with lower risk of MACE. Children had multi-systemic disorders with severe outcome, suggesting that the diagnostic and clinical approaches should be adjusted to age at presentation. The observed genotype-phenotype correlations endorsed that DNA diagnostics for NCCM is important for clinical management and counseling of patients.
Topics: Adolescent; Adult; Age Factors; Cardiomyopathies; Child; Child, Preschool; Female; Genetic Association Studies; Heart Diseases; Humans; Infant; Male; Risk Assessment; Sarcomeres; Young Adult
PubMed: 31771441
DOI: 10.1161/JAHA.119.012993 -
The Journal of Physiology Aug 2022The force-pCa (F-pCa) curve is used to characterize steady-state contractile properties of cardiac muscle cells in different physiological, pathological and...
The force-pCa (F-pCa) curve is used to characterize steady-state contractile properties of cardiac muscle cells in different physiological, pathological and pharmacological conditions. This provides a reduced preparation in which to isolate sarcomere mechanisms. However, it is unclear how changes in the F-pCa curve impact emergent whole-heart mechanics quantitatively. We study the link between sarcomere and whole-heart function using a multiscale mathematical model of rat biventricular mechanics that describes sarcomere, tissue, anatomy, preload and afterload properties quantitatively. We first map individual cell-level changes in sarcomere-regulating parameters to organ-level changes in the left ventricular function described by pressure-volume loop characteristics (e.g. end-diastolic and end-systolic volumes, ejection fraction and isovolumetric relaxation time). We next map changes in the sarcomere-regulating parameters to changes in the F-pCa curve. We demonstrate that a change in the F-pCa curve can be caused by multiple different changes in sarcomere properties. We demonstrate that changes in sarcomere properties cause non-linear and, importantly, non-monotonic changes in left ventricular function. As a result, a change in sarcomere properties yielding changes in the F-pCa curve that improve contractility does not guarantee an improvement in whole-heart function. Likewise, a desired change in whole-heart function (i.e. ejection fraction or relaxation time) is not caused by a unique shift in the F-pCa curve. Changes in the F-pCa curve alone cannot be used to predict the impact of a compound on whole-heart function. KEY POINTS: The force-pCa (F-pCa) curve is used to assess myofilament calcium sensitivity after pharmacological modulation and to infer pharmacological effects on whole-heart function. We demonstrate that there is a non-unique mapping from changes in F-pCa curves to changes in left ventricular (LV) function. The effect of changes in F-pCa on LV function depend on the state of the heart and could be different for different pathological conditions. Screening of compounds to impact whole-heart function by F-pCa should be combined with active tension and calcium transient measurements to predict better how changes in muscle function will impact whole-heart physiology.
Topics: Animals; Calcium; Myocardial Contraction; Myocytes, Cardiac; Myofibrils; Rats; Sarcomeres
PubMed: 35737959
DOI: 10.1113/JP283352 -
Archives of Biochemistry and Biophysics Feb 2019Current inotropic therapies improve systolic function in heart failure patients but also elicit undesirable side effects such as arrhythmias and increased intracellular... (Review)
Review
Current inotropic therapies improve systolic function in heart failure patients but also elicit undesirable side effects such as arrhythmias and increased intracellular Ca transients. In order to maintain myocyte Ca homeostasis, the increased cytosolic Ca needs to be actively transported back to sarcoplasmic reticulum leading to depleted ATP reserves. Thus, an emerging approach is to design sarcomere-based treatments to correct impaired contractility via a direct and allosteric modulation of myosin's intrinsic force-generating behavior -a concept that potentially avoids the "off-target" effects. To achieve this goal, various biophysical approaches are utilized to investigate the mechanistic impact of sarcomeric modulators but information derived from diverse approaches is not fully integrated into therapeutic applications. This is in part due to the lack of information that provides a coherent connecting link between biophysical data to in vivo function. Hence, our ability to clearly discern the drug-mediated impact on whole-heart function is diminished. Reducing this translational barrier can significantly accelerate clinical progress related to sarcomere-based therapies by optimizing drug-dosing and treatment duration protocols based on information obtained from biophysical studies. Therefore, we attempt to link biophysical mechanical measurements obtained in isolated cardiac muscle and in vivo contractile function.
Topics: Animals; Cardiotonic Agents; Heart Failure; Humans; Myocardial Contraction; Myocardium; Sarcomeres; Translational Research, Biomedical
PubMed: 30576628
DOI: 10.1016/j.abb.2018.12.021