Disease mutations in striated muscle myosins

Parker, Francine; Peckham, Michelle

doi:10.1007/s12551-020-00721-5

Cited by 30 publications

(28 citation statements)

References 37 publications

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“…Comparing the myopathy mutations listed by Parker and Peckham [ 14 ], 6 mutations occur in the 16 sites we found to be associated with mass (p adj < 0.05) but not with clade. Each of these myopathy sites have a different substitution to the one found across mammals except R434K.…”

Section: Resultsmentioning

confidence: 54%

“… Blue lines show the frequency of missense variation present in the gnomAD. Circles indicate the residue position of variants associated with cardiomyopathy (HCMs in orange, DCMs in magenta, and other in green [ 14 ]). Black lines show the frequency with which the consensus amino acid occurs at each residue position in the sequence.…”

Section: Resultsmentioning

confidence: 99%

“…The 52 common sites of variation between species were of interest to compare with amino acids in human β-myosin implicated in myopathies (hypertrophic cardiomyopathies [HCMs], dilated cardiomyopathies [DCMs], and other cardiomyopathies as orange, magenta, and green dots in Fig 3 [ 14 ]). More than half the sites in the motor domain (approximately 500/800) have been found to have mutations linked to myopathies, but only 20 out of the 52 sites identified to differ among mammals are common between the 2 groups.…”

Section: Resultsmentioning

confidence: 99%

“…Residues associated with cardiomyopathies were obtained from Parker and Peckham [ 14 ] and compared to the residues associated with body mass by considering exact matches to residues associated with cardiomyopathy. These were grouped into HCM, DCM, and other.…”

Section: Methodsmentioning

confidence: 99%

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Identification of sequence changes in myosin II that adjust muscle contraction velocity

et al. 2021

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The speed of muscle contraction is related to body size; muscles in larger species contract at slower rates. Since contraction speed is a property of the myosin isoform expressed in a muscle, we investigated how sequence changes in a range of muscle myosin II isoforms enable this slower rate of muscle contraction. We considered 798 sequences from 13 mammalian myosin II isoforms to identify any adaptation to increasing body mass. We identified a correlation between body mass and sequence divergence for the motor domain of the 4 major adult myosin II isoforms (β/Type I, IIa, IIb, and IIx), suggesting that these isoforms have adapted to increasing body mass. In contrast, the non-muscle and developmental isoforms show no correlation of sequence divergence with body mass. Analysis of the motor domain sequence of β-myosin (predominant myosin in Type I/slow and cardiac muscle) from 67 mammals from 2 distinct clades identifies 16 sites, out of 800, associated with body mass (padj < 0.05) but not with the clade (padj > 0.05). Both clades change the same small set of amino acids, in the same order from small to large mammals, suggesting a limited number of ways in which contraction velocity can be successfully manipulated. To test this relationship, the 9 sites that differ between human and rat were mutated in the human β-myosin to match the rat sequence. Biochemical analysis revealed that the rat–human β-myosin chimera functioned like the native rat myosin with a 2-fold increase in both motility and in the rate of ADP release from the actin–myosin crossbridge (the step that limits contraction velocity). Thus, these sequence changes indicate adaptation of β-myosin as species mass increased to enable a reduced contraction velocity and heart rate.

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Section: Resultsmentioning

confidence: 54%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Identification of sequence changes in myosin II that adjust muscle contraction velocity

et al. 2021

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“…In contrast to the MYH7 gene that encodes the ventricular/slow myosin heavy chain β isoform, MYH6 encodes the myosin heavy chain α isoform that is predominantly expressed in human cardiac atrium. Mutations in MYH6, although relatively rare, have been associated with both HCM and DCM (Schiaffino and Reggiani, 1996;Parker and Peckham, 2020). In a zebrafish heart, there are three major MYH homologs: atrial myosin heavy chain (amhc, also termed myh6), ventricular myosin heavy chain (vmhc), and ventricular myosin heavy chain-like (vmhcl) (Auman et al, 2007).…”

Section: Myh6mentioning

confidence: 99%

Modeling Inherited Cardiomyopathies in Adult Zebrafish for Precision Medicine

Ding

2020

Front. Physiol.

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Cardiomyopathies are a highly heterogeneous group of heart muscle disorders. More than 100 causative genes have been linked to various cardiomyopathies, which explain about half of familial cardiomyopathy cases. More than a dozen candidate therapeutic signaling pathways have been identified; however, precision medicine is not being used to treat the various types of cardiomyopathy because knowledge is lacking for how to tailor treatment plans for different genetic causes. Adult zebrafish (Danio rerio) have a higher throughout than rodents and are an emerging vertebrate model for studying cardiomyopathy. Herein, we review progress in the past decade that has proven the feasibility of this simple vertebrate for modeling inherited cardiomyopathies of distinct etiology, identifying effective therapeutic strategies for a particular type of cardiomyopathy, and discovering new cardiomyopathy genes or new therapeutic strategies via a forward genetic approach. On the basis of this progress, we discuss future research that would benefit from integrating this emerging model, including discovery of remaining causative genes and development of genotype-based therapies. Studies using this efficient vertebrate model are anticipated to significantly accelerate the implementation of precision medicine for inherited cardiomyopathies.

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New paradigms in actomyosin energy transduction: Critical evaluation of non‐traditional models for orthophosphate release

et al. 2023

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Release of the ATP hydrolysis product ortophosphate (Pi) from the active site of myosin is central in chemo‐mechanical energy transduction and closely associated with the main force‐generating structural change, the power‐stroke. Despite intense investigations, the relative timing between Pi‐release and the power‐stroke remains poorly understood. This hampers in depth understanding of force production by myosin in health and disease and our understanding of myosin‐active drugs. Since the 1990s and up to today, models that incorporate the Pi‐release either distinctly before or after the power‐stroke, in unbranched kinetic schemes, have dominated the literature. However, in recent years, alternative models have emerged to explain apparently contradictory findings. Here, we first compare and critically analyze three influential alternative models proposed previously. These are either characterized by a branched kinetic scheme or by partial uncoupling of Pi‐release and the power‐stroke. Finally, we suggest critical tests of the models aiming for a unified picture.

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Disease mutations in striated muscle myosins

Cited by 30 publications

References 37 publications

Identification of sequence changes in myosin II that adjust muscle contraction velocity

Identification of sequence changes in myosin II that adjust muscle contraction velocity

Modeling Inherited Cardiomyopathies in Adult Zebrafish for Precision Medicine

New paradigms in actomyosin energy transduction: Critical evaluation of non‐traditional models for orthophosphate release

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