A model of crossbridge action: the effects of ATP, ADP and Pi

Pate, Edward; Cooke, Roger

doi:10.1007/bf01739809

Cited by 240 publications

(262 citation statements)

References 54 publications

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“…They found that skeletal muscle myosin ATPase action was far less susceptible to ADP inhibition than either cardiac or smooth muscle myosin, and calculated that the approximate K i value (measured as competitive inhibition by ADP with respect to ATP) of skeletal muscle actomyosin was an order of magnitude greater than that of cardiac or smooth muscle. It is widely felt that the free [ADP] in skeletal muscle in vivo is insufficiently high to cause myosin ATPase inhibition [45]. Conversely, in cardiac muscle, ventilation under mild hypoxia (8Ϫ10% O 2 ) can cause [ADP] to increase into the range where significant ATPase inhibition has been observed to occur in vitro [44].…”

Section: Discussionmentioning

confidence: 99%

A control analysis exploration of the role of ATP utilisation in glycolytic‐flux control and glycolytic‐metabolite‐concentration regulation

Thomas

Fell

1998

European Journal of Biochemistry

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A theoretical metabolic-control-analysis approach has been used to study aspects of glycolytic-flux control and carbon-metabolite regulation, particularly the role of ATP demand (ATPase), in order to determine what general features of the regulation of energy metabolism would be consistent with good carbon-metabolite homeostasis in the face of large changes in carbon flux. On the basis of a semiquantitative control-analysis model, incorporating estimates of substrate, product and effector actions on the enzymes, the experimentally observed characteristics of glycolytic-flux changes prove to impose constraints on the feasible ranges of these estimates. This leads to the identification of several features of energy metabolism, each of which is necessary but not sufficient to explain the observations; although most of these have been advocated previously (such as AMP activation of phosphofructokinase (PFK), ADP inhibition of ATPase and the role of energy charge or ATP/ADP ratio), our analysis allows their relative importance to be assessed. In the model, the distribution of flux control depends primarily on ADP inhibition of ATPase, and on the activation of PFK by AMP; increase in ADP inhibition of ATPase increases the control on PFK; increase in AMP activation of PFK increases control on ATPase. PFK exerts greater flux control than does ATPase over approximately 50% of the ranges (parameter space) studied, but its control is sufficiently high to achieve sizeable flux increases over less than 20% of the space. Furthermore, control by alteration in PFK activity is shown to result in poor glycolytic metabolite homeostasis over the entire parameter space studied. However, over a large proportion of the parameter space, control by activation of ATPase can lead to large flux changes, i.e. high flux control, coupled with excellent glycolytic-metabolite homeostasis, similar to that observed in working muscle. As well as altering the relative degrees of flux control invested in PFK and ATPase, ADP inhibition of ATPase and AMP activation of PFK have pronounced effects on the homeostatic properties of the system. Stronger ADP inhibition of ATPase results in improved homeostasis of glycolytic metabolites, ATP and ADP in response to PFK activation, whereas stronger activation of PFK by AMP improves the homeostasis of these three quantities in response to ATPase activation. The results are further evidence of the potential for physiological ATP demand to exert control over glycolytic flux, but additionally show that the known effector interactions, in addition to their previously known role in ATP regulation, could contribute to the remarkable homeostasis of glycolytic-metabolite levels observed in vivo. They further indicate that quantitative characterisation of likely domains of behaviour of metabolic systems can be achieved by an algebraic analysis that is not highly dependent on a full and precise knowledge of the molecular details of the kinetic/regulatory properties of the enzymes, but that still allows an assessment of w...

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Section: Discussionmentioning

confidence: 99%

A control analysis exploration of the role of ATP utilisation in glycolytic‐flux control and glycolytic‐metabolite‐concentration regulation

Thomas

Fell

1998

European Journal of Biochemistry

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“…It is likely that venous occlusion limited removal of metabolic products from the exercising ECR muscle. Among metabolic products, H+ and Pi are known to cause fatigue [8,27,29]. Furthermore, increase in H+ ion concentration has been demonstrated to produce a larger force reduction in the type IIb fibers compared to type I fibers [XI, and the ECR muscle is predominantly composed of type IIb fibers [I?].…”

Section: Discussionmentioning

confidence: 99%

Ischemia causes muscle fatigue

Murthy

Hargens

Lehman

et al. 2001

Journal Orthopaedic Research

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Tlie purpose of this investigation was to determine whether iscliemia, which reduces oxygenation in the extensor carpi radialis (ECR) muscle, causes a reduction in muscle force production. In eight subjects, muscle oxygenation (TOz) of the right ECR was measured noninvasively and continuously using near infrared spectroscopy (NIRS) while muscle twitch force was elicited by transcutaneous electrical stimulation ( 1 Hz, 0.1 ms). Baseline measurements of blood volume, muscle oxygenation and twitch force were recorded continuously, then a tourniquet on the upper arm was inflated to one of five different pressure levels: 20, 40, 60 mm Hg (randomized order) and diastolic (69 * 9.8 mm Hg) and systolic (106 f 12.8 mm Hg) blood pressures. Each pressure level was maintained for 3-5 niin, and was followed by a recovery period sufficient to allow measurements to return to baseline. For each respective tourniquet pressure level, mean TO2 decreased from resting baseline ( 100% TO?) to 99 f 1.2% (SEM), 96 f I .9'% 93 f 2.8%. 90 2~ 2.5%, and 86 i 2.7'!4, and mean twitch force decreased from resting baseline (100% force) to 99 f 0.7'/'0 (SEM), 96 i 2.7'%1, 93 j , 3.1'J/~~, 88 & 3.2'!'11, and 86 & 2.6' /11. Muscle oxygenation and twitch force at 60 mm Hg tourniquet compression and above were significantly lower ( P < 0.05) than baseline value. Reduced twitch force was correlated in a dose-dependent manner with reduced muscle oxygenation ( I , = 0.78,P < 0.001). Although the correlation does not prove causation, the results indicate that ischemia leading to a 7'90 or greater reduction in muscle oxygenation causes decreased muscle force production in the forearm extensor muscle. Thus, ischemia associated with a modest decline in TOz causes muscle fatigue.

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“…First, at low ATP concentrations an increase in inorganic phosphate (P i ) to 50 mM caused a significant decrease in unloaded shortening velocity (20). Second, when fiber stiffness of isometrically contracting fibers was measured at different speeds of stretch, the stiffness-speed relations recorded in the presence of 5-10 mM P i were shifted to slower stretch velocities (21).…”

Section: In Addition Phosphate Did Not Extend Dwell Times Of Cy3-edamentioning

confidence: 99%

Inorganic Phosphate Binds to the Empty Nucleotide Binding Pocket of Conventional Myosin II

Amrute-Nayak

Antognozzi

Scholz

et al. 2008

Journal of Biological Chemistry

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In muscle inorganic phosphate strongly decreases force generation in the presence of millimolar MgATP, whereas phosphate slows shortening velocity only at micromolar MgATP concentrations. It is still controversial whether reduction in shortening velocity by phosphate results from phosphate binding to the nucleotide-free myosin head or from binding of phosphate to an actomyosin-ADP state as postulated for the inhibition of force generation by phosphate. Because most single-molecule studies are performed at micromolar concentrations of MgATP where phosphate effects on movement are rather prominent, clarification of the mechanisms of phosphate inhibition is essential for interpretation of data in which phosphate is used in single molecule studies to probe molecular events of force generation and movement. In in vitro assays we found that inhibition of filament gliding by inorganic phosphate was associated with increased fragmentation of actin filaments. In addition, phosphate did not extend dwell times Muscle contraction involves the sliding of actin filaments relative to myosin filaments (1, 2), which is driven by cyclic interactions of the myosin head domains with the actin filaments, powered by hydrolysis of ATP. During each ATP-hydrolysis cycle chemical energy of ATP hydrolysis is transformed into mechanical work by a multistep power-stroke which drives the actin filaments several nanometers past the myosin filaments. The power-stroke is associated with the release of the ATP hydrolysis products, P i (inorganic phosphate) and ADP, from the active site (3). It is generally believed that P i release from the AM⅐ADP⅐P i 3 complex is closely related to the initiation of the power-stroke (4) and to the transition of the myosin head domain from states of weak and non-stereospecific actin binding to states of strong and stereospecific binding to actin (5-7). Because of the assumed close relation between power stroke and the release of inorganic phosphate from the myosin head domain, studying the effects of inorganic phosphate on contracting muscle fibers became a main element to elucidate the relation between P i release and force generation. Effects of P i were examined on isometric force (4, 8 -14) and unloaded shortening velocity (9, 13, 15) as well as on force transients in response to release of P i from caged P i (16,17). As a result of these studies it was proposed that inhibition of active force by inorganic phosphate results from rebinding of P i to the AM⅐ADP intermediate that is formed after P i release (cf. Scheme 1). Thus, the release of phosphate is reversed and a strong binding force generating cross-bridges in the AM⅐ADP state are reversed to a weak binding non-force generating AM⅐ADP⅐P i state (the AM⅐ADP⅐Pi I state in Scheme 1) that is in rapid equilibrium with the detached M⅐ADP⅐P i I intermediate. To fully account for the observed steady state kinetic data and the force transients recorded upon release of P i from caged P i , it was proposed that a strong binding AM⅐ADP⅐P i intermediate (the AM⅐AD...

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A model of crossbridge action: the effects of ATP, ADP and Pi

Cited by 240 publications

References 54 publications

A control analysis exploration of the role of ATP utilisation in glycolytic‐flux control and glycolytic‐metabolite‐concentration regulation

A control analysis exploration of the role of ATP utilisation in glycolytic‐flux control and glycolytic‐metabolite‐concentration regulation

Ischemia causes muscle fatigue

Inorganic Phosphate Binds to the Empty Nucleotide Binding Pocket of Conventional Myosin II

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