Matching Mechanics and Energetics of Muscle Contraction Suggests Unconventional Chemomechanical Coupling during the Actin–Myosin Interaction

Pertici, Irene; Bongini, Lorenzo; Caremani, Marco; Reconditi, Massimo; Linari, Marco; Piazzesi, Gabriella; Lombardi, Vincenzo; Bianco, Pasquale

doi:10.3390/ijms241512324

Cited by 2 publications

(1 citation statement)

References 57 publications

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“…Specifically, parameter a is the internal force against which unloaded muscle shortens, and b is the product of the myosin step size, d, and the actin-myosin ATPase rate [15,18]. Ignoring this thermodynamic model and centuries of thermodynamics preceding it, corpuscularians have for over 65 years created one new molecular power stroke model after another, each describing different mechanisms for a and b, none of which are consistent with the basic underlying physical chemistry (most recently [31]). No attempts are made to test one proposed corpuscular mechanism against another because the strain-dependent corpuscular kinetics arbitrarily defined to fit muscle force-velocity curves are non-physical and will never be observed experimentally.…”

Section: Thermodynamics Is Inconsistent With Corpuscular Mechanicsmentioning

confidence: 99%

The Problem with Inventing Molecular Mechanisms to Fit Thermodynamic Equations of Muscle

Baker

2023

IJMS

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Almost every model of muscle contraction in the literature to date is a molecular power stroke model, even though this corpuscular mechanism is opposed by centuries of science, by 85 years of unrefuted evidence that muscle is a thermodynamic system, and by a quarter century of direct observations that the molecular mechanism of muscle contraction is a molecular switch, not a molecular power stroke. An ensemble of molecular switches is a binary mechanical thermodynamic system from which A.V. Hill’s muscle force–velocity relationship is directly derived, where Hill’s parameter a is the internal force against which unloaded muscle shortens, and Hill’s parameter b is the product of the switch displacement, d, and the actin–myosin ATPase rate. Ignoring this model and the centuries of thermodynamics that preceded it, corpuscularians continue to develop molecular power stroke models, adding to their 65-year jumble of “new”, “innovative”, and “unconventional” molecular mechanisms for Hill’s a and b parameters, none of which resemble the underlying physical chemistry. Remarkably, the corpuscularian community holds the thermodynamicist to account for these discrepancies, which, as outlined here, I have done for 25 years. It is long past time for corpuscularians to be held accountable for their mechanisms, which by all accounts have no foundation in science. The stakes are high. Molecular power stroke models are widely used in research and in clinical decision-making and have, for over half a century, muddied our understanding of the inner workings of one of the most efficient and clean-burning machines on the planet. It is problematic that corpuscularians present these models to stakeholders as science when in fact corpuscularians have been actively defending these models against science for decades. The path forward for scientists is to stop baseless rejections of muscle thermodynamics and to begin testing corpuscular and thermodynamic mechanisms with the goal of disproving one or the other of these hypotheses.

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Section: Thermodynamics Is Inconsistent With Corpuscular Mechanicsmentioning

confidence: 99%

The Problem with Inventing Molecular Mechanisms to Fit Thermodynamic Equations of Muscle

Baker

2023

IJMS

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Stochastic Force Generation in an Isometric Binary Mechanical System: A Thermodynamic Model of Muscle Force Generation

Murthy,

Baker

2023

Preprint

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With implications for both clean energy technologies and human health, models of muscle contraction provide insights into the inner workings of one of the most energy efficient engines on the planet and into the modifications to that engine that lead to human diseases. However, only scientific methods can provide these insights. A binary mechanical model is a recently developed thermodynamic model of muscle contraction that implies a novel entropic kinetic formalism, provides a solution to a paradox that has perplexed scientists for over a century, and accounts for many mechanical and energetic aspects of muscle contraction. Here we use this model to perform discrete state chemical simulations of isometric force generation under different conditions and show explicitly that force generating kinetics are bounded by thermodynamic equations, that four phases of force generation occur as four separate thermodynamic processes, and that periodic force generation emerges with amplitudes and ergodicities that bifurcate between constant and stochastic values through mechanisms easily understood relative to ideal thermodynamic processes. We discuss these results relative to experimental observations of spontaneous oscillatory contractions (SPOCs) in muscle and periodic force generation in small myosin ensembles.

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Matching Mechanics and Energetics of Muscle Contraction Suggests Unconventional Chemomechanical Coupling during the Actin–Myosin Interaction

Cited by 2 publications

References 57 publications

The Problem with Inventing Molecular Mechanisms to Fit Thermodynamic Equations of Muscle

The Problem with Inventing Molecular Mechanisms to Fit Thermodynamic Equations of Muscle

Stochastic Force Generation in an Isometric Binary Mechanical System: A Thermodynamic Model of Muscle Force Generation

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