-
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 -
Soft Matter Apr 2022Muscle cells with sarcomeric structure exhibit highly non trivial passive mechanical response. The difficulty of its continuum modeling is due to the presence of...
Muscle cells with sarcomeric structure exhibit highly non trivial passive mechanical response. The difficulty of its continuum modeling is due to the presence of long-range interactions transmitted by extended protein skeleton. To build a rheological model for muscle 'material', we use a stochastic micromodel, and derive a linear response theory for a half-sarcomere, which can be extended to the whole fibre. Instead of the first order rheological equation, anticipated by Hill on the phenomenological grounds, we obtain a novel second order equation which shows that tension depends not only on its current length and the velocity of stretching, but also on its acceleration. Expressing the model in terms of elementary rheological elements, we show that one contribution to the visco-elastic properties of the fibre originates in cross-bridges, while the other can be linked to inert elements which move in the sarcoplasm. We apply this model to explain the striking qualitative difference between the relaxation in experiments involving perturbation of length those involving perturbation of force, and we use the values of the microscopic parameters for frog muscles to show that the model is in excellent quantitative agreement with physiological experiments.
Topics: Muscle Contraction; Muscle, Skeletal; Sarcomeres; Viscosity
PubMed: 35388379
DOI: 10.1039/d1sm01527c -
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 -
Archives of Biochemistry and Biophysics Jul 2021A highly organized and densely packed lattice of molecular machinery within the sarcomeres of muscle cells powers contraction. Although many of the proteins that drive...
A highly organized and densely packed lattice of molecular machinery within the sarcomeres of muscle cells powers contraction. Although many of the proteins that drive contraction have been studied extensively, the mechanical impact of fluid shearing within the lattice of molecular machinery has received minimal attention. It was recently proposed that fluid flow augments substrate transport in the sarcomere, however, this analysis used analytical models of fluid flow in the molecular machinery that could not capture its full complexity. By building a finite element model of the sarcomere, we estimate the explicit flow field, and contrast it with analytical models. Our results demonstrate that viscous drag forces on sliding filaments are surprisingly small in contrast to the forces generated by single myosin molecular motors. This model also indicates that the energetic cost of fluid flow through viscous shearing with lattice proteins is likely minimal. The model also highlights a steep velocity gradient between sliding filaments and demonstrates that the maximal radial fluid velocity occurs near the tips of the filaments. To our knowledge, this is the first computational analysis of fluid flow within the highly structured sarcomere.
Topics: Animals; Biomechanical Phenomena; Computer Simulation; Finite Element Analysis; Humans; Models, Biological; Muscle Contraction; Myosins; Rheology; Sarcomeres; Thermodynamics; Viscosity
PubMed: 34029559
DOI: 10.1016/j.abb.2021.108923 -
Neuroscience and Biobehavioral Reviews May 2022We reviewed the responses of the neuromuscular properties of mainly the soleus and possible mechanisms. Sensory nervous activity in response to passive shortening and/or... (Review)
Review
We reviewed the responses of the neuromuscular properties of mainly the soleus and possible mechanisms. Sensory nervous activity in response to passive shortening and/or active contraction, associated with plantar-flexion or dorsi-flexion of the ankle joints, may play an essential role in the regulation of muscle properties. Passive shortening of the muscle fibers and sarcomeres inhibits the development of tension, electromyogram (EMG), and afferent neurogram. Remodeling of the sarcomeres, which decreases the total sarcomere number in a single muscle fiber causing recovery of the length in each sarcomere, is induced in the soleus following chronic unloading. Although EMG activity and tension development in each sarcomere are increased, the total tension produced by the whole muscle is still less owing to the lower sarcomere number. Therefore, muscle atrophy continues to progress. Moreover, walking or slow running by rear-foot strike landing with the application of greater ground reaction force, which stimulates soleus mobilization, could be an effective countermeasure. Periodic, but not chronic, passive stretching of the soleus may also be effective.
Topics: Electromyography; Humans; Muscle, Skeletal; Sarcomeres; Space Flight; Walking
PubMed: 35283170
DOI: 10.1016/j.neubiorev.2022.104617 -
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 -
The American Journal of Cardiology Feb 2024Genetic testing is an important tool in the diagnosis and management of patients and families with hypertrophic cardiomyopathy (HCM). Modern testing can identify...
Genetic testing is an important tool in the diagnosis and management of patients and families with hypertrophic cardiomyopathy (HCM). Modern testing can identify causative variants in 30 to >60% of patients, with probability of a positive test varying with baseline characteristics such as known family history of HCM. Patients diagnosed with HCM should be offered genetic counseling and genetic testing as appropriate. Standard multigene panels evaluate sarcomeric genes known to cause HCM as well as genetic conditions that can mimic HCM but require different management. Positive genetic testing (finding a pathogenic or likely pathogenic variant) helps to clarify diagnosis and assists in family screening. If there is high confidence that an identified variant is the cause of HCM, at-risk family members can pursue predictive testing to determine if they are truly at risk or if they can be dismissed from serial screening based on whether they inherited the family's causative variant. Interpreting test results can be complex, and providers should make use of multidisciplinary teams as well as evidence-based resources to obtain the best possible understanding of pathogenicity.
Topics: Humans; Genetic Testing; Cardiomyopathy, Hypertrophic; Genetic Counseling; Family; Sarcomeres; Mutation
PubMed: 38368035
DOI: 10.1016/j.amjcard.2023.10.032 -
Journal of Cellular Physiology Jun 2019Limb-girdle muscular dystrophies (LGMDs) are a highly heterogeneous group of neuromuscular disorders that are associated with weakness and wasting of muscles in legs and... (Review)
Review
Limb-girdle muscular dystrophies (LGMDs) are a highly heterogeneous group of neuromuscular disorders that are associated with weakness and wasting of muscles in legs and arms. Signs and symptoms may begin at any age and usually worsen by time. LGMDs are autosomal disorders with different types and their prevalence is not the same in different areas. New technologies such as next-generation sequencing can accelerate their diagnosis. Several important pathological mechanisms that are involved in the pathology of the LGMD include abnormalities in dystrophin-glycoprotein complex, the sarcomere, glycosylation of dystroglycan, vesicle and molecular trafficking, signal transduction pathways, and nuclear functions. Here, we provide a comprehensive review that integrates LGMD clinical manifestations, prevalence, and some pathological mechanisms involved in LGMDs.
Topics: Cachexia; High-Throughput Nucleotide Sequencing; Humans; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Neuromuscular Diseases; Sarcomeres
PubMed: 30536378
DOI: 10.1002/jcp.27907 -
Vascular Pharmacology Aug 2022Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder that associates with nucleotide sequence variants in genes encoding sarcomere related proteins, and... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder that associates with nucleotide sequence variants in genes encoding sarcomere related proteins, and is recognized as the most common heritable cardiac diseases. Clinically, HCM can be extremely variable and this makes the diagnosis difficult until the development of serious or fatal events. Nevertheless, the main hallmark of HCM is represented by left ventricle hypertrophy that can be occasionally associated to cardiac arrhythmias, chest pain, diastolic dysfunction, obstruction of left ventricular outflow tract. The present review aims to focus on the complex interplay existing between the multifaceted non-genetic molecular mechanisms underlying HCM onset and progression, and the key pathophysiological role of abnormal coronary artery function. As the clinical course of HCM shows a mortality rate per year up to 6% the importance of innovative therapeutic strategies will be discussed, especially in regard to the use of potential endogenous coronary modulators to be enrolled as modifiers of HCM phenotype.
Topics: Cardiomyopathy, Hypertrophic; Heart; Humans; Hypertrophy, Left Ventricular; Phenotype; Sarcomeres
PubMed: 35680059
DOI: 10.1016/j.vph.2022.107003 -
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