The myosin-activated thin filament regulatory state, M − -open: a link to hypertrophic cardiomyopathy (HCM)

Lehrer, Sherwin S.; Geeves, Michael A.

doi:10.1007/s10974-014-9383-z

Cited by 31 publications

(31 citation statements)

References 53 publications

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“…Tm in the thin filament interacts with seven actin subunits and with itself end-to-end, forming a continuous strand along actin. The cooperative unit size, n, in the reconstituted thin filament (actin 7 TmTn), however, was shown to be n ¼ 10-12, due to strong end-to-end interactions facilitated by Tn (20). The greater duration of the slow phase of relaxation for the mutants observed here suggests a greater communication between neighboring structural units, with a bound head at one actin site keeping many neighboring sites open via a more rigid Tm.…”

Section: D137l and D137l/g126r Tm Interactions In The Thin Filamentmentioning

confidence: 68%

“…The apparent increase in the Ca 2þ sensitivity of tension (Fig. 6), however, is due to the contribution of the residual tension produced by the M À state, which decreases as the [Ca 2þ ] increases (20).…”

Section: Relaxation Impairment and The Three-state Theorymentioning

confidence: 94%

“…At the same time, functional studies have indicated that when cTnI is present in the Tn complex, crossbridge formation in the absence of Ca 2þ is not fully inhibited, with impaired inhibition of the resting ATPase of reconstituted cardiac systems (46), impaired relaxation, and an apparent increase in the Ca 2þ sensitivity of replaced cardiac myofibrils (31). Similar effects were produced with the TnI HCM mutant R146W-cTnI (47), which appeared to shift the equilibrium away from the blocked state (20). Interestingly, cross-linking (22) and structural (48) data show an interaction of TnI with Tm in the absence of Ca 2þ .…”

Section: D137l and D137l/g126r Tm Interactions In The Thin Filamentmentioning

confidence: 95%

“…The greater duration of the slow phase of relaxation for the mutants observed here suggests a greater communication between neighboring structural units, with a bound head at one actin site keeping many neighboring sites open via a more rigid Tm. For these mutants, it would be interesting to verify this proposed mechanism for the change in n by conducting in vitro kinetic studies on reconstituted thin filaments with labeled Tm, as previously performed on native systems (20).…”

Section: D137l and D137l/g126r Tm Interactions In The Thin Filamentmentioning

confidence: 96%

“…The data were very similar to what was observed by replacing cardiac TnI (cTnI) with a C-terminal truncated form of cTnI in skeletal myofibrils. Both sets of data can be explained by the increased contribution of an active open state in the absence of Ca 2þ (M À (20)) according to the three-state muscle regulation theory (21). Furthermore, our results support the hypotheses that the local and long-range flexibility of the Tm coiled-coil structure, as well as some interactions of the Tm central part with TnI (2,22) and/or myosin (16), may be crucial to maintain the full inhibition of acto-myosin interactions of the resting state.…”

Section: Introductionmentioning

confidence: 99%

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The Relaxation Properties of Myofibrils Are Compromised by Amino Acids that Stabilize α-Tropomyosin

Scellini

Piroddi

Matyushenko

et al. 2017

Biophysical Journal

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We investigated the functional impact of a-tropomyosin (Tm) substituted with one (D137L) or two (D137L/ G126R) stabilizing amino acid substitutions on the mechanical behavior of rabbit psoas skeletal myofibrils by replacing endogenous Tm and troponin (Tn) with recombinant Tm mutants and purified skeletal Tn. Force recordings from myofibrils (15 C) at saturating [Ca 2þ ] showed that Tm-stabilizing substitutions did not significantly affect the maximal isometric tension and the rates of force activation (k ACT ) and redevelopment (k TR ). However, a clear effect was observed on force relaxation: myofibrils with D137L/G126R or D137L Tm showed prolonged durations of the slow phase of relaxation and decreased rates of the fast phase. Both Tm-stabilizing substitutions strongly decreased the slack sarcomere length (SL) at submaximal activating [Ca 2þ ] and increased the steepness of the SL-passive tension relation. These effects were reversed by addition of 10 mM 2,3-butanedione 2-monoxime. Myofibrils also showed an apparent increase in Ca 2þ sensitivity. Measurements of myofibrillar ATPase activity in the absence of Ca 2þ showed a significant increase in the presence of these Tms, indicating that single and double stabilizing substitutions compromise the full inhibition of contraction in the relaxed state. These data can be understood with . This work provides a basis for understanding the effects of disease-producing mutations in muscle proteins.

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Section: D137l and D137l/g126r Tm Interactions In The Thin Filamentmentioning

confidence: 68%

Section: Relaxation Impairment and The Three-state Theorymentioning

confidence: 94%

Section: D137l and D137l/g126r Tm Interactions In The Thin Filamentmentioning

confidence: 95%

Section: D137l and D137l/g126r Tm Interactions In The Thin Filamentmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Relaxation Properties of Myofibrils Are Compromised by Amino Acids that Stabilize α-Tropomyosin

Scellini

Piroddi

Matyushenko

et al. 2017

Biophysical Journal

Self Cite

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Generative adversarial networks for construction of virtual populations of mechanistic models: simulations to study Omecamtiv Mecarbil action

Parikh

Rumbell

Butova

et al. 2021

J Pharmacokinet Pharmacodyn

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Biophysical models are increasingly used to gain mechanistic insights by fitting and reproducing experimental and clinical data. The inherent variability in the recorded datasets, however, presents a key challenge. In this study, we present a novel approach, which integrates mechanistic modeling and machine learning to analyze in vitro cardiac mechanics data and solve the inverse problem of model parameter inference. We designed a novel generative adversarial network (GAN) and employed it to construct virtual populations of cardiac ventricular myocyte models in order to study the action of Omecamtiv Mecarbil (OM), a positive cardiac inotrope. Populations of models were calibrated from mechanically unloaded myocyte shortening recordings obtained in experiments on rat myocytes in the presence and absence of OM. The GAN was able to infer model parameters while incorporating prior information about which model parameters OM targets. The generated populations of models reproduced variations in myocyte contraction recorded during in vitro experiments and provided improved understanding of OM’s mechanism of action. Inverse mapping of the experimental data using our approach suggests a novel action of OM, whereby it modifies interactions between myosin and tropomyosin proteins. To validate our approach, the inferred model parameters were used to replicate other in vitro experimental protocols, such as skinned preparations demonstrating an increase in calcium sensitivity and a decrease in the Hill coefficient of the force–calcium (F–Ca) curve under OM action. Our approach thereby facilitated the identification of the mechanistic underpinnings of experimental observations and the exploration of different hypotheses regarding variability in this complex biological system.

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Pathomechanisms in heart failure: the contractile connection

Stienen

2014

J Muscle Res Cell Motil

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Heart failure is a multi-factorial progressive disease in which eventually the contractile performance of the heart is insufficient to meet the demands of the body, even at rest. A distinction can be made on the basis of the cause of the disease in genetic and acquired heart failure and at the functional level between systolic and diastolic heart failure. Here the basic determinants of contractile function of myocardial cells will be reviewed and an attempt will be made to elucidate their role in the development of heart failure. The following topics are addressed: the tension generating capacity, passive tension, the rate of tension development, the rate of ATP utilisation, calcium sensitivity of tension development, phosphorylation of contractile proteins, length dependent activation and stretch activation. The reduction in contractile performance during systole can be attributed predominantly to a loss of cardiomyocytes (necrosis), myocyte disarray and a decrease in myofibrillar density all resulting in a reduction in the tension generating capacity and likely also to a mismatch between energy supply and demand of the myocardium. This leads to a decline in the ejection fraction of the heart. Diastolic dysfunction can be attributed to fibrosis and an increase in titin stiffness which result in an increase in stiffness of the ventricular wall and hampers the filling of the heart with blood during diastole. A large number of post translation modifications of regulatory sarcomeric proteins influence myocardial function by altering calcium sensitivity of tension development. It is still unclear whether in concert these influences are adaptive or maladaptive during the disease process.

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The myosin-activated thin filament regulatory state, M − -open: a link to hypertrophic cardiomyopathy (HCM)

Cited by 31 publications

References 53 publications

The Relaxation Properties of Myofibrils Are Compromised by Amino Acids that Stabilize α-Tropomyosin

The Relaxation Properties of Myofibrils Are Compromised by Amino Acids that Stabilize α-Tropomyosin

Generative adversarial networks for construction of virtual populations of mechanistic models: simulations to study Omecamtiv Mecarbil action

Pathomechanisms in heart failure: the contractile connection

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