Contractility parameters of human β-cardiac myosin with the hypertrophic cardiomyopathy mutation R403Q show loss of motor function

Nag, Suman; Sommese, Ruth F.; Ujfalusi, Zoltán; Combs, Ariana C.; Langer, Shelby L.; Sutton, Shirley; Leinwand, Leslie A.; Geeves, Michael A.; Ruppel, Kathleen M.; Spudich, James A.

doi:10.1126/sciadv.1500511

Cited by 115 publications

(186 citation statements)

References 70 publications

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“…This value is 100 s −1 (20) for SKM, which is 4.5-fold slower than the fitted k −AD mentioned above. For CMM, the fitted value of k −AD (139 ± 4 s −1 ) ( Table 1) is too fast by a factor of~2, considering that both stopped-flow and single-molecule determinations of k −AD are relatively similar at~50 to 80 s −1 (32,(36)(37)(38)(39) under similar conditions (40). In summary, the best fits to a detachmentlimited model generally require r to be lower and k −AD to be higher than measured values.…”

Section: S C I E N C E a D V A N C E S | R E S E A R C H A R T I C L Ementioning

confidence: 99%

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A Mixed-Kinetic Model Describes Unloaded Velocities of Smooth, Skeletal, and Cardiac Muscle Myosin Filaments in Vitro

Brizendine

Sheehy

Alcala

et al. 2018

Biophysical Journal

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In vitro motility assays, where purified myosin and actin move relative to one another, are used to better understand the mechanochemistry of the actomyosin adenosine triphosphatase (ATPase) cycle. We examined the relationship between the relative velocity (V) of actin and myosin and the number of available myosin heads (N) or [ATP] for smooth (SMM), skeletal (SKM), and cardiac (CMM) muscle myosin filaments moving over actin as well as V from actin filaments moving over a bed of monomeric SKM. These data do not fit well to a widely accepted model that predicts that V is limited by myosin detachment from actin (d/t on ), where d equals step size and t on equals time a myosin head remains attached to actin. To account for these data, we have developed a mixed-kinetic model where V is influenced by both attachment and detachment kinetics. The relative contributions at a given V vary with the probability that a head will remain attached to actin long enough to reach the end of its flexible S2 tether. Detachment kinetics are affected by L/t on , where L is related to the tether length. We show that L is relatively long for SMM, SKM, and CMM filaments (59 ± 3 nm, 22 ± 9 nm, and 22 ± 2 nm, respectively). In contrast, L is shorter (8 ± 3 nm) when myosin monomers are attached to a surface. This suggests that the behavior of the S2 domain may be an important mechanical feature of myosin filaments that influences unloaded shortening velocities of muscle.

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Section: S C I E N C E a D V A N C E S | R E S E A R C H A R T I C L Ementioning

confidence: 99%

“…For all fits to CMM data, fixed values are as follows: fig. S1C), d = 8 nm, and k −AD = 50 s −1 (32,(36)(37)(38)(39). Filament assays § N was fixed at 88 based on average filament length and Eq.…”

Section: S C I E N C E a D V A N C E S | R E S E A R C H A R T I C L Ementioning

confidence: 99%

A Mixed-Kinetic Model Describes Unloaded Velocities of Smooth, Skeletal, and Cardiac Muscle Myosin Filaments in Vitro

Brizendine

Sheehy

Alcala

et al. 2018

Biophysical Journal

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“…The R403Q-MyHC mutation in the mouse α-myosin motor domain, which some reports indicate is a molecular gain-of-function mutation with supra-normal ATPase activity, leads to left ventricular (LV) hypertrophy, heart failure, and/or arrhythmias (13,16,35,36). However, another report studying the human cardiac β-myosin motor shows a loss of function in some parameters (37). In contrast, the R92W-TnT mutation confers increased Ca 2+ sensitivity to muscle fiber contraction and predisposes to cardiac fibrosis and ventricular arrhythmias/sudden cardiac death at a young age, in the absence of significant hypertrophy (38,39).…”

Section: Introductionmentioning

confidence: 99%

Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models

Vakrou

Fukunaga²,

Foster

et al. 2018

JCI Insight

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“…This observation emphasizes the importance of understanding the mechanisms that underlie cardiac hypercontractility caused by MHC and cMyBPC mutations, and how these functional defects can be reversed or normalized using genetic or pharmacological approaches 12. Missense mutations in human cardiac β‐MHC result in variable effects on contractile function including reduced13, 14 or enhanced intrinsic force generation15, 16; decreased14, 16 or enhanced15 myosin ATPase activity; and accelerated13, 15, 17 or slowed16 actin sliding velocities. Importantly, recent data show that HCM‐causing mutations in β‐MHC that cause hypercontractility weaken myosin's S1‐S2 intradomain interactions, thus effectively increasing the total number of myosin heads that can interact with actin during systole,11 thereby chronically elevating left ventricular ejection fraction 5, 18.…”

Section: Introductionmentioning

confidence: 99%

Impact of the Myosin Modulator Mavacamten on Force Generation and Cross‐Bridge Behavior in a Murine Model of Hypercontractility

Mamidi

Doh

et al. 2018

JAHA

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BackgroundRecent studies suggest that mavacamten (Myk461), a small myosin‐binding molecule, decreases hypercontractility in myocardium expressing hypertrophic cardiomyopathy‐causing missense mutations in myosin heavy chain. However, the predominant feature of most mutations in cardiac myosin binding protein‐C (cMyBPC) that cause hypertrophic cardiomyopathy is reduced total cMyBPC expression, and the impact of Myk461 on cMyBPC‐deficient myocardium is currently unknown.Methods and ResultsWe measured the impact of Myk461 on steady‐state and dynamic cross‐bridge (XB) behavior in detergent‐skinned mouse wild‐type myocardium and myocardium lacking cMyBPC (knockout (KO)). KO myocardium exhibited hypercontractile XB behavior as indicated by significant accelerations in rates of XB detachment (krel) and recruitment (kdf) at submaximal Ca2+ activations. Incubation of KO and wild‐type myocardium with Myk461 resulted in a dose‐dependent force depression, and this impact was more pronounced at low Ca2+ activations. Interestingly, Myk461‐induced force depressions were less pronounced in KO myocardium, especially at low Ca2+ activations, which may be because of increased acto‐myosin XB formation and potential disruption of super‐relaxed XBs in KO myocardium. Additionally, Myk461 slowed krel in KO myocardium but not in wild‐type myocardium, indicating increased XB “on” time. Furthermore, the greater degree of Myk461‐induced slowing in kdf and reduction in XB recruitment magnitude in KO myocardium normalized the XB behavior back to wild‐type levels.ConclusionsThis is the first study to demonstrate that Myk461‐induced force depressions are modulated by cMyBPC expression levels in the sarcomere, and emphasizes that clinical use of Myk461 may need to be optimized based on the molecular trigger that underlies the hypertrophic cardiomyopathy phenotype.

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Contractility parameters of human β-cardiac myosin with the hypertrophic cardiomyopathy mutation R403Q show loss of motor function

Abstract: Force parameters of human β-cardiac myosin with the hypertrophic cardiomyopathy mutation R403Q show loss of molecular motor function.

Cited by 115 publications

References 70 publications

A Mixed-Kinetic Model Describes Unloaded Velocities of Smooth, Skeletal, and Cardiac Muscle Myosin Filaments in Vitro

A Mixed-Kinetic Model Describes Unloaded Velocities of Smooth, Skeletal, and Cardiac Muscle Myosin Filaments in Vitro

Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models

Impact of the Myosin Modulator Mavacamten on Force Generation and Cross‐Bridge Behavior in a Murine Model of Hypercontractility

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