A new myofilament contraction model with ATP consumption for ventricular cell model

Muangkram, Yuttamol; Noma, Akinori; Amano, Atsushi

doi:10.1007/s12576-017-0560-x

Cited by 7 publications

(5 citation statements)

References 77 publications

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“…Only 60% of this concentration was assumed to be available for actomyosin cross-bridge cycling based on previous estimates of ATP usage in cardiac muscle. 32…”

Section: Methodsmentioning

confidence: 99%

Defects in the Proteome and Metabolome in Human Hypertrophic Cardiomyopathy

Previs

O’Leary

Morley

et al. 2022

Circ: Heart Failure

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BACKGROUND: Defects in energetics are thought to be central to the pathophysiology of hypertrophic cardiomyopathy (HCM); yet, the determinants of ATP availability are not known. The purpose of this study is to ascertain the nature and extent of metabolic reprogramming in human HCM, and its potential impact on contractile function. METHODS: We conducted proteomic and targeted, quantitative metabolomic analyses on heart tissue from patients with HCM and from nonfailing control human hearts. RESULTS: In the proteomic analysis, the greatest differences observed in HCM samples compared with controls were increased abundances of extracellular matrix and intermediate filament proteins and decreased abundances of muscle creatine kinase and mitochondrial proteins involved in fatty acid oxidation. These differences in protein abundance were coupled with marked reductions in acyl carnitines, byproducts of fatty acid oxidation, in HCM samples. Conversely, the ketone body 3-hydroxybutyrate, branched chain amino acids, and their breakdown products, were all significantly increased in HCM hearts. ATP content, phosphocreatine, nicotinamide adenine dinucleotide and its phosphate derivatives, NADP and NADPH, and acetyl CoA were also severely reduced in HCM compared with control hearts. Functional assays performed on human skinned myocardial fibers demonstrated that the magnitude of observed reduction in ATP content in the HCM samples would be expected to decrease the rate of cross-bridge detachment. Moreover, left atrial size, an indicator of diastolic compliance, was inversely correlated with ATP content in hearts from patients with HCM. CONCLUSIONS: HCM hearts display profound deficits in nucleotide availability with markedly reduced capacity for fatty acid oxidation and increases in ketone bodies and branched chain amino acids. These results have important therapeutic implications for the future design of metabolic modulators to treat HCM.

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“…Only 60% of this concentration was assumed to be available for actomyosin cross-bridge cycling based on previous estimates of ATP usage in cardiac muscle. 32…”

Section: Methodsmentioning

confidence: 99%

Defects in the Proteome and Metabolome in Human Hypertrophic Cardiomyopathy

Previs

O’Leary

Morley

et al. 2022

Circ: Heart Failure

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“…while for w = 0.5 we have J B (3nl M À2 ) À3/8 . In eqn (29) we can deduce that largely swollen gels are made of softer polymers, having smaller nl M À2 , and/or polymers composed of chains that have high affinity with solvent molecules, thus smaller (more negative) w.…”

Section: Chemo-mechanical Equilibriummentioning

confidence: 99%

“…These values are equivalent to approximately 1.3 ATP molecules consumed per myosin head per second in the timespan of one hour, as detailed in Appendix C. Experimental observations reported 0.5-5 ATP molecules consumed per myosin head per second. 29 Because w M estimates the effective work produced by the MM, the real ATP energy consumed is expected to be higher. The MM efficiency in this case can be estimated from a minimum of 1.3/5 = 26% to a maximum of 1.3/0.5 = 86%.…”

Section: Experimental Comparisonmentioning

confidence: 99%

Energetics of cytoskeletal gel contraction

et al. 2023

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“…Only 60% of this concentration was assumed to be available for actomyosin cross-bridge cycling based on previous estimates of ATP usage in cardiac muscle. 30…”

Section: Estimation Of Atp Concentration In Vivomentioning

confidence: 99%

Metabolic and Proteomic Defects in Human Hypertrophic Cardiomyopathy

Previs

O’Leary

Wood

et al. 2021

Preprint

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RationaleImpaired cardiac energetics in hypertrophic cardiomyopathy (HCM) is thought to result from increased ATP utilization at the sarcomere and is believed to be central to pathophysiology. However, the precise defects in cardiac metabolism and substrate availability in human HCM have not been defined.ObjectiveThe purpose of this study is to define major disease pathways and determine the pool sizes of intermediary metabolites in human HCM.Methods and ResultsWe conducted paired proteomic and metabolomic analyses of septal myectomy samples from patients with HCM and compared results to non-failing control human hearts. Increased abundance of extracellular matrix and intermediate filament / Z-disc proteins, and decreased abundance of proteins involved in fatty acid oxidation and cardiac energetics was evident in HCM compared to controls. Acyl carnitines, byproducts of fatty acid oxidation, were markedly depleted in HCM samples. Conversely, the ketone body 3-hydroxybutyrate, lactate, and the 3 branched chain amino acids, were all significantly increased in HCM hearts, suggesting that they may serve as alternate fuel sources for the production of ATP. ATP, nicotinamide adenine dinucleotide (NADH), NADP and NADPH, and acetyl CoA were also severely depleted in HCM hearts. Based on measurements from human skinned muscle fibers, the magnitude of observed reduction in ATP content in the HCM hearts would be expected to decrease the rate of cross-bridge detachment, implying a direct effect of energy depletion on myofilament function that could contribute to diastolic dysfunction.ConclusionsHCM hearts display profound deficits in cardiac energetics, marked by depletion of fatty acid derivatives and compensatory increases in other metabolites that could serve as alternate fuel sources. These results lend support to the paradigm that energy depletion contributes to the pathophysiology of HCM and also have important therapeutic implications for the future design of metabolic modulators to treat HCM.

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A new myofilament contraction model with ATP consumption for ventricular cell model

Cited by 7 publications

References 77 publications

Defects in the Proteome and Metabolome in Human Hypertrophic Cardiomyopathy

Defects in the Proteome and Metabolome in Human Hypertrophic Cardiomyopathy

Energetics of cytoskeletal gel contraction

Metabolic and Proteomic Defects in Human Hypertrophic Cardiomyopathy

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