Towards a Unified Theory of Muscle Contraction. I: Foundations

Smith, David A.; Geeves, Michael A.; Sleep, John; Mijailovich, Srboljub M.

doi:10.1007/s10439-008-9536-6

Cited by 78 publications

(95 citation statements)

References 85 publications

(133 reference statements)

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“…3) that the application of a load causes a reduction in the K M for sliding velocity (Table 2). A strainsensitive ATP-binding step for myosin has previously been suggested for muscle (18,25,26) and nonmuscle myosins (19,21).…”

Section: Discussionmentioning

confidence: 96%

Cardiomyopathy-linked myosin regulatory light chain mutations disrupt myosin strain-dependent biochemistry

Greenberg

Kazmierczak

Szczesna‐Cordary

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Familial hypertrophic cardiomyopathy (FHC) is caused by mutations in sarcomeric proteins including the myosin regulatory light chain (RLC). Two such FHC mutations, R58Q and N47K, located near the cationic binding site of the RLC, have been identified from population studies. To examine the molecular basis for the observed phenotypes, we exchanged endogenous RLC from native porcine cardiac myosin with recombinant human ventricular wild type (WT) or FHC mutant RLC and examined the ability of the reconstituted myosin to propel actin filament sliding using the in vitro motility assay. We find that, whereas the mutant myosins are indistinguishable from the controls (WT or native myosin) under unloaded conditions, both R58Q-and N47K-exchanged myosins show reductions in force and power output compared with WT or native myosin. We also show that the changes in loaded kinetics are a result of mutation-induced loss of myosin strain sensitivity of ADP affinity. We propose that the R58Q and N47K mutations alter the mechanical properties of the myosin neck region, leading to altered loaddependent kinetics that may explain the observed mutant-induced FHC phenotypes.in vitro motility | load-dependent kinetics | familial hypertrophic cardiomyopathy | R58Q | N47K F amilial hypertrophic cardiomyopathy (FHC), the leading cause of sudden cardiac death in people under 30 (1), is characterized by several changes in cardiac structure including myofibrillar disarray and thickening of the left ventricle, papillary muscles, and/or septum. FHC is a disease of the sarcomere, resulting from mutations of cardiac proteins (reviewed in refs. 1 and 2) including the regulatory (RLC) and essential (ELC) light chains of myosin.Each myosin molecule is a hexamer composed of two myosin heavy chains (MHC), two RLCs, and two ELCs (3). The α-helical neck region of the MHC has been proposed to act as a lever arm, amplifying small conformational changes that originate at the myosin catalytic site into large movements needed to produce contractile force. The α-helical neck, supported by the two light chains, has been proposed to function as a compliant element (4-6), with the light chains imparting stiffness to the lever arm. Therefore, disruption of the light chain binding to the MHC could conceivably impair force generation as well as the transmission of external loads to the myosin active site, leading to a loss of myosin strain sensitivity.The RLC is a calmodulin homology protein that contains an EF-hand Ca 2+ -Mg 2+ binding site and also a highly conserved phosphorylatable serine, both sites located at the N terminus of the RLC. It has also been shown that both phosphorylation of the RLC (7, 8) and the presence of bound cation (9) play important roles in the structure and function of myosin, reinforcing the notion that there is a high degree of interdomain communication between these sites.Given the functional importance of the RLC-containing neck domain of myosin, it is not surprising that mutations of the RLC can cause FHC. Population studies have i...

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Section: Discussionmentioning

confidence: 96%

Cardiomyopathy-linked myosin regulatory light chain mutations disrupt myosin strain-dependent biochemistry

Greenberg

Kazmierczak

Szczesna‐Cordary

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Comparing the thick curve in figure 5a with the experimental observation of the T 2 curve (open symbols) shows the model to be successful in predicting the width of the curve, but the shape matches only approximately. The likely reason for the poor match in shape is that the constraints on the attachment of crossbridges owing to (i) different longitudinal spacing of actin and myosin sites (Huxley & Tideswell 1996;Smith et al 2008) and (ii) effects of filament compliance on the proximity of actin and myosin sites (Smith et al 2005) have not been included here.…”

Section: Proc R Soc B (2009)mentioning

confidence: 99%

“…biochemical). Partly for want of this mapping, there is no quantitative standard theory of muscle contraction, which can model the results of many different types of experiment (Smith et al 2008). Because certain steps in the cycle are strongly temperature dependent, the application of the methods described below can help with the mapping problem.…”

Section: Introductionmentioning

confidence: 99%

Temperature change as a probe of muscle crossbridge kinetics: a review and discussion

2009

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Following the ideas introduced by Huxley (Huxley 1957, Prog. Biophys. Biophys. Chem. 7, 255-318), it is generally supposed that muscle contraction is produced by temporary links, called crossbridges, between myosin and actin filaments, which form and break in a cyclic process driven by ATP splitting. Here we consider the interaction of the energy in the crossbridge, in its various states, and the force exerted. We discuss experiments in which the mechanical state of the crossbridge is changed by imposed movement and the energetic consequence observed as heat output and the converse experiments in which the energy content is changed by altering temperature and the mechanical consequences are observed. The thermodynamic relationship between the experiments is explained and, at the first sight, the relationship between the results of these two types of experiment appears paradoxical. However, we describe here how both of them can be explained by a model in which mechanical and energetic changes in the crossbridges occur in separate steps in a branching cycle.

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“…Future research in this area will target at incorporating more realistic models at micro level, i.e. Duke (1999) and Smith et al (2007).…”

Section: Resultsmentioning

confidence: 99%

High performance computing in multi-scale modeling, graph science and meta-heuristic optimization

Ivanović¹,

Stojanović²,

Simic³

et al. 2016

J Serb Soc Comp Mech

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One of the main activities within the Group for Scientific Computing at the Faculty of Science are methods for efficiently utilizing real parallel architectures, typically clusters of SMP nodes, shared-memory systems, and GPUs. Focus is on the design, development and implementation of parallel algorithms and data structures for fundamental scientific and engineering problems. Message Passing Interface (MPI) is an important paradigm that still poses interesting design and implementation problems, especially combined with other programming models, like CUDA. In addition to standard HPC (High Performance Computing) technology stack, the Group also utilizes computing stacks like Hadoop and Spark. In this paper we present a short review of the recent research of the Group, focused on large-scale applications in various research fields with references to original articles. The first part considers multi-scale muscle modeling in mixed MPI-CUDA environment. In our approach, a finite element macro model is coupled with the microscopic Huxley kinetics model. The original approach in scheduling tasks within multi-scale simulation ensures good load balance, leading to speed-up of over two orders of magnitude and high scalability. The second part considers application of HPC in graph science for the task of establishing the basic structural features of the minimum-ABC index trees. In order to analyze large amounts of data (all trees of certain order) we utilize grid computing services like storage and computing in order to reduce analysis time up to three orders of magnitude. The last part presents WoBinGO framework for solving optimization problems on HPC resources. It overcomes the shortcomings of earlier static pilot-job frameworks by providing elastic resource provisioning using adaptive allocation of jobs with limited lifetime. The obtained results show that despite WoBinGO's adaptive and frugal allocation of computing resources, it provides significant speed-up when dealing with problems with computationally expensive evaluations, as found in hydro-informatics and market risk management.

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Towards a Unified Theory of Muscle Contraction. I: Foundations

Cited by 78 publications

References 85 publications

Cardiomyopathy-linked myosin regulatory light chain mutations disrupt myosin strain-dependent biochemistry

Cardiomyopathy-linked myosin regulatory light chain mutations disrupt myosin strain-dependent biochemistry

Temperature change as a probe of muscle crossbridge kinetics: a review and discussion

High performance computing in multi-scale modeling, graph science and meta-heuristic optimization

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