Effects of myosin light chain phosphorylation on length-dependent myosin kinetics in skinned rat myocardium

Pulcastro, Hannah C.; Awinda, Peter O.; Breithaupt, Jason J.; Tanner, Bertrand C.W.

doi:10.1016/j.abb.2015.12.014

Cited by 21 publications

(38 citation statements)

References 77 publications

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“…When comparing trabeculae with reduced and increased phosphorylation, the rate of f is accelerated ß20 fold at each SL, whereas g is only accelerated ß1.6 fold. A recent study suggests that RLC phosphorylation slows cross-bridge detachment (g), which does not fit the modelling of our experimental data and contradicts the existing literature (Pulcastro et al 2016). The discrepancy may result from the different experimental and modelling approaches for the study of cross-bridge kinetics.…”

Section: Modelling Of Cross-bridge Attachment (F) and Detachment (G)contrasting

confidence: 99%

“…A recent study suggests that RLC phosphorylation slows cross‐bridge detachment ( g ), which does not fit the modelling of our experimental data and contradicts the existing literature (Pulcastro et al . ). The discrepancy may result from the different experimental and modelling approaches for the study of cross‐bridge kinetics.…”

Section: Discussionmentioning

confidence: 97%

“…Perhaps the phosphorylation state of other sarcomeric proteins is also different from that achieved in the present study (Pulcastro et al . ).…”

Section: Discussionmentioning

confidence: 97%

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Revisiting Frank–Starling: regulatory light chain phosphorylation alters the rate of force redevelopment (k_tr) in a length‐dependent fashion

Toepfer

West

Ferenczi

2016

The Journal of Physiology

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Key points Regulatory light chain (RLC) phosphorylation has been shown to alter the ability of muscle to produce force and power during shortening and to alter the rate of force redevelopment (k tr) at submaximal [Ca2+].Increasing RLC phosphorylation ∼50% from the in vivo level in maximally [Ca2+]‐activated cardiac trabecula accelerates k tr.Decreasing RLC phosphorylation to ∼70% of the in vivo control level slows k tr and reduces force generation. k tr is dependent on sarcomere length in the physiological range 1.85–1.94 μm and RLC phosphorylation modulates this response.We demonstrate that Frank–Starling is evident at maximal [Ca2+] activation and therefore does not necessarily require length‐dependent change in [Ca2+]‐sensitivity of thin filament activation.The stretch response is modulated by changes in RLC phosphorylation, pinpointing RLC phosphorylation as a modulator of the Frank–Starling law in the heart.These data provide an explanation for slowed systolic function in the intact heart in response to RLC phosphorylation reduction. AbstractForce and power in cardiac muscle have a known dependence on phosphorylation of the myosin‐associated regulatory light chain (RLC). We explore the effect of RLC phosphorylation on the ability of cardiac preparations to redevelop force (k tr) in maximally activating [Ca2+]. Activation was achieved by rapidly increasing the temperature (temperature‐jump of 0.5–20ºC) of permeabilized trabeculae over a physiological range of sarcomere lengths (1.85–1.94 μm). The trabeculae were subjected to shortening ramps over a range of velocities and the extent of RLC phosphorylation was varied. The latter was achieved using an RLC‐exchange technique, which avoids changes in the phosphorylation level of other proteins. The results show that increasing RLC phosphorylation by 50% accelerates k tr by ∼50%, irrespective of the sarcomere length, whereas decreasing phosphorylation by 30% slows k tr by ∼50%, relative to the k tr obtained for in vivo phosphorylation. Clearly, phosphorylation affects the magnitude of k tr following step shortening or ramp shortening. Using a two‐state model, we explore the effect of RLC phosphorylation on the kinetics of force development, which proposes that phosphorylation affects the kinetics of both attachment and detachment of cross‐bridges. In summary, RLC phosphorylation affects the rate and extent of force redevelopment. These findings were obtained in maximally activated muscle at saturating [Ca2+] and are not explained by changes in the Ca2+‐sensitivity of acto‐myosin interactions. The length‐dependence of the rate of force redevelopment, together with the modulation by the state of RLC phosphorylation, suggests that these effects play a role in the Frank–Starling law of the heart.

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Section: Modelling Of Cross-bridge Attachment (F) and Detachment (G)contrasting

confidence: 99%

Section: Discussionmentioning

confidence: 97%

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Revisiting Frank–Starling: regulatory light chain phosphorylation alters the rate of force redevelopment (k_tr) in a length‐dependent fashion

Toepfer

West

Ferenczi

2016

The Journal of Physiology

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“…These studies suggest that the gradient of RLC phosphorylation supports the cardiac torsional movement and thus facilitates overall cardiac contraction. Interestingly, a recent study in rat heart shows that an increase in RLC phosphorylation slows down the rates of both cross-bridge MgADP release and MgATP binding at 1.9-µm sarcomere length, whereas only slows down cross-bridge MgATP binding at 2.2-µm sarcomere length with no effects on the rate of MgADP release (Pulcastro et al 2016). This indicates that RLC phosphorylation has a differential role on cross-bridge kinetics depending on sarcomere length.…”

Section: Structure Isoforms Phosphorylation Sites and Function Of Rlcmentioning

confidence: 99%

Phosphorylation of the regulatory light chain of myosin in striated muscle: methodological perspectives

Chakravorty

Song

et al. 2016

Eur Biophys J

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Phosphorylation of the regulatory light chain (RLC) of myosin modulates cellular functions such as muscle contraction, mitosis, and cytokinesis. Phosphorylation defects are implicated in a number of diseases. Here we focus on striated muscle where changes in RLC phosphorylation relate to diseases such as hypertrophic cardiomyopathy and muscular dystrophy, or age-related changes. RLC phosphorylation in smooth muscle and non-muscle cells are covered briefly where relevant. There is much scientific interest in controlling the phosphorylation levels of RLC in vivo and in vitro in order to understand its physiological function in striated muscles. A summary of available and emerging in vivo and in vitro methods is presented. The physiological role of RLC phosphorylation and novel pathways are discussed to highlight the differences between muscle types and to gain insights into disease processes.

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“…These data suggest that the rapid length-dependent effects on myosin cycling kinetics result from intrinsic properties of the myofilament rather than PKA or PKC signaling mediated phosphorylation. Work from the laboratory of Bertrand Tanner investigated the effects of length on myosin RLC phosphorylation regulated contractile function (7). Measurements in skinned cardiac muscle preparations demonstrated both RLC phosphorylation and sarcomere length increased calcium sensitivity and decreased the cross-bridge cycling rate, however the effect of RLC phosphorylation to slow the rate of cross-bridge MgATP binding was greater at increased sarcomere lengths.…”

mentioning

confidence: 99%

Myofilament modulation of contraction

Biesiadecki

2016

Archives of Biochemistry and Biophysics

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Effects of myosin light chain phosphorylation on length-dependent myosin kinetics in skinned rat myocardium

Cited by 21 publications

References 77 publications

Revisiting Frank–Starling: regulatory light chain phosphorylation alters the rate of force redevelopment (k_tr) in a length‐dependent fashion

Revisiting Frank–Starling: regulatory light chain phosphorylation alters the rate of force redevelopment (k_tr) in a length‐dependent fashion

Phosphorylation of the regulatory light chain of myosin in striated muscle: methodological perspectives

Myofilament modulation of contraction

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Effects of myosin light chain phosphorylation on length-dependent myosin kinetics in skinned rat myocardium

Cited by 21 publications

References 77 publications

Revisiting Frank–Starling: regulatory light chain phosphorylation alters the rate of force redevelopment (ktr) in a length‐dependent fashion

Revisiting Frank–Starling: regulatory light chain phosphorylation alters the rate of force redevelopment (ktr) in a length‐dependent fashion

Phosphorylation of the regulatory light chain of myosin in striated muscle: methodological perspectives

Myofilament modulation of contraction

Contact Info

Product

Resources

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Revisiting Frank–Starling: regulatory light chain phosphorylation alters the rate of force redevelopment (k_tr) in a length‐dependent fashion

Revisiting Frank–Starling: regulatory light chain phosphorylation alters the rate of force redevelopment (k_tr) in a length‐dependent fashion