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Dilated cardiomyopathy myosin mutants have reduced force-generating capacity.

ABSTRACT: Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) can cause arrhythmias, heart failure, and cardiac death. Here, we functionally characterized the motor domains of five DCM-causing mutations in human ?-cardiac myosin. Kinetic analyses of the individual events in the ATPase cycle revealed that each mutation alters different steps in this cycle. For example, different mutations gave enhanced or reduced rate constants of ATP binding, ATP hydrolysis, or ADP release or exhibited altered ATP, ADP, or actin affinity. Local effects dominated, no common pattern accounted for the similar mutant phenotype, and there was no distinct set of changes that distinguished DCM mutations from previously analyzed HCM myosin mutations. That said, using our data to model the complete ATPase contraction cycle revealed additional critical insights. Four of the DCM mutations lowered the duty ratio (the ATPase cycle portion when myosin strongly binds actin) because of reduced occupancy of the force-holding A·M·D complex in the steady state. Under load, the A·M·D state is predicted to increase owing to a reduced rate constant for ADP release, and this effect was blunted for all five DCM mutations. We observed the opposite effects for two HCM mutations, namely R403Q and R453C. Moreover, the analysis predicted more economical use of ATP by the DCM mutants than by WT and the HCM mutants. Our findings indicate that DCM mutants have a deficit in force generation and force-holding capacity due to the reduced occupancy of the force-holding state.

SUBMITTER: Ujfalusi Z

PROVIDER: S-EPMC5995530 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Dilated cardiomyopathy myosin mutants have reduced force-generating capacity.

Ujfalusi Zoltan Z Vera Carlos D CD Mijailovich Srbolujub M SM Svicevic Marina M Yu Elizabeth Choe EC Kawana Masataka M Ruppel Kathleen M KM Spudich James A JA Geeves Michael A MA Leinwand Leslie A LA

The Journal of biological chemistry 20180417 23

Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) can cause arrhythmias, heart failure, and cardiac death. Here, we functionally characterized the motor domains of five DCM-causing mutations in human β-cardiac myosin. Kinetic analyses of the individual events in the ATPase cycle revealed that each mutation alters different steps in this cycle. For example, different mutations gave enhanced or reduced rate constants of ATP binding, ATP hydrolysis, or ADP release or exhibited alte ...[more]

PMID: 29666183

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Project description:Background:This study analyzes the myocardial force-generating capacity in infective endocarditis (IE) using an experimental model of isolated human atrial myocardium. In vivo, it is difficult to decide whether or not alterations in myocardial contractile behavior are due to secondary effects associated with infection such as an altered heart rate, alterations of preload and afterload resulting from valvular defects, and altered humoral processes. Our in vitro model using isolated human myocardium, in contrast, guarantees exactly defined experimental conditions with respect to preload, afterload, and contraction frequency, thus not only preventing confounding by in vivo determinants of contractility but also excluding effects of other factors associated with sepsis, hemodynamics, humoral influences, temperature, and medical treatment. Methods:We analyzed right atrial trabeculae (diameter 0.3-0.5 mm, initial length 5 mm) from 32 patients undergoing aortic and/or mitral valve replacement for acute valve incompetence caused by IE and 65 controls receiving aortic and/or mitral valve replacement for nonendocarditic valve incompetence. Isometric force amplitudes and passive resting force values measured at optimal length in the two groups were compared using Student's t-test. Results:There were no significant differences between the groups in terms of the passive resting force. The isometric force amplitude in the endocarditis group, however, was significantly lower than in the nonendocarditis group (p=0.001). In the endocarditis group, the calculated active force, defined as the isometric force amplitude minus the resting force, was significantly lower (p<0.0001) and the resting force/active force ratio was significantly higher (p<0.0001). Using linear regression to describe the function between resting force and active force, we identified a significant difference in slope (p<0.0001), with lower values found in the endocarditis group. Conclusion:Our data suggest that the force-generating capacity of atrial myocardium is significantly reduced in patients with IE. In these patients, an elevated resting force is required to achieve a given force amplitude. It remains unclear, however, whether this is due to calcium desensitization of the contractile apparatus, presence of myocardial edema, fibrotic remodeling, disruption of contractile units, or other mechanisms.

Project description:Skeletal muscle mass, architecture and force-generating capacity are well known to scale with body size in animals, both throughout ontogeny and across species. Investigations of limb muscle scaling in terrestrial amniotes typically focus on individual muscles within select clades, but here this question was examined at the level of the whole limb across amniotes generally. In particular, the present study explored how muscle mass, force-generating capacity (measured by physiological cross-sectional area) and internal architecture (fascicle length) scales in the fore- and hindlimbs of extant mammals, non-avian saurians ('reptiles') and bipeds (birds and humans). Sixty species spanning almost five orders of magnitude in body mass were investigated, comprising previously published architectural data and new data obtained via dissections of the opossum Didelphis virginiana and the tegu lizard Salvator merianae. Phylogenetic generalized least squares was used to determine allometric scaling slopes (exponents) and intercepts, to assess whether patterns previously reported for individual muscles or functional groups were retained at the level of the whole limb, and to test whether mammals, reptiles and bipeds followed different allometric trajectories. In general, patterns of scaling observed in individual muscles were also observed in the whole limb. Reptiles generally have proportionately lower muscle mass and force-generating capacity compared to mammals, especially at larger body size, and bipeds exhibit strong to extreme positive allometry in the distal hindlimb. Remarkably, when muscle mass was accounted for in analyses of muscle force-generating capacity, reptiles, mammals and bipeds almost ubiquitously followed a single common scaling pattern, implying that differences in whole-limb force-generating capacity are principally driven by differences in muscle mass, not internal architecture. In addition to providing a novel perspective on skeletal muscle allometry in animals, the new dataset assembled was used to generate pan-amniote statistical relationships that can be used to predict muscle mass or force-generating capacity in extinct amniotes, helping to inform future reconstructions of musculoskeletal function in the fossil record.

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Dilated cardiomyopathy myosin mutants have reduced force-generating capacity.

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Dilated cardiomyopathy myosin mutants have reduced force-generating capacity.

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