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J Physiol. 2016 Sep 15;594(18):5237-54. doi: 10.1113/JP272441. Epub 2016 Jul 24.

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

Author information

1
Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London, UK. christopher_toepfer@HMS.harvard.edu.
2
Laboratory of Molecular Physiology, NHLBI, National Institutes of Health, Bethesda, MD, USA. christopher_toepfer@HMS.harvard.edu.
3
Structure & Motion Laboratory, Royal Veterinary College London, North Mymms, UK.
4
Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London, UK.
5
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.

Abstract

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 (ktr ) at submaximal [Ca(2+) ]. Increasing RLC phosphorylation ∼50% from the in vivo level in maximally [Ca(2+) ]-activated cardiac trabecula accelerates ktr . Decreasing RLC phosphorylation to ∼70% of the in vivo control level slows ktr and reduces force generation. ktr 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 [Ca(2+) ] activation and therefore does not necessarily require length-dependent change in [Ca(2+) ]-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.

ABSTRACT:

Force 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 (ktr ) in maximally activating [Ca(2+) ]. 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 ktr by ∼50%, irrespective of the sarcomere length, whereas decreasing phosphorylation by 30% slows ktr by ∼50%, relative to the ktr obtained for in vivo phosphorylation. Clearly, phosphorylation affects the magnitude of ktr 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 [Ca(2+) ] and are not explained by changes in the Ca(2+) -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.

KEYWORDS:

cardiac muscle; force redevelopment; muscle contraction; phosphorylation; regulatory light chain

PMID:
27291932
PMCID:
PMC5023691
DOI:
10.1113/JP272441
[Indexed for MEDLINE]
Free PMC Article

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