Regulatory Light Chains of Striated Muscle Myosin. Structure, Function and Malfunction

Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, FL 33136, USA.
Current Drug Targets - Cardiovascular & Hematological Disorders 07/2003; 3(2):187-97. DOI: 10.2174/1568006033481474
Source: PubMed


Striated (skeletal and cardiac) muscle is activated by the binding of Ca(2+) to troponin C and is regulated by the thin filament proteins, tropomyosin and troponin. Unlike in molluscan or smooth muscles, the myosin regulatory light chains (RLC) of striated muscles do not play a major regulatory role and their function is still not well understood. The N-terminal domain of RLC contains a 'Ca(2+)-Mg(2+)'-binding site and, analogous to that of smooth muscle myosin, also contains a phosphorylation site. During muscle contraction, the increase in Ca(2+) concentration activates the Ca(2+)/calmodulin-dependent myosin light chain kinase and leads to phosphorylation of the RLC. In agreement with other laboratories we have demonstrated that phosphorylation and Ca(2+) binding to the RLC play an important modulatory role in striated muscle contraction. Furthermore, the ventricular isoform of human cardiac RLC has been shown to be one of the sarcomeric proteins associated with familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disease characterized by left ventricular hypertrophy, myofibrillar disarray and sudden cardiac death. Our recent studies have demonstrated that phosphorylation and Ca(2+) binding to human ventricular RLC are significantly altered by the FHC mutations and that their detrimental effects depend upon the specific position of the missense mutation, whether located in the proximity of the RLC 'Ca(2+)-Mg(2+)'-binding site or the phosphorylation site (Serine 15). We have also shown that there is a functional coupling between Ca(2+) and/or Mg(2+) binding to the RLC and phosphorylation and that the FHC mutations can affect this relationship. Further in vivo studies are necessary to investigate the mechanisms involved in the pathogenesis of RLC-linked FHC.

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Available from: Danuta Szczesna-Cordary
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    • "There are three major theories that explain the underlying physiological mechanisms of PAP [1]. One of the most consistent theories states that prior stimulation phosphorylates the myosin's regulatory light chains, moving them away from the myosin thick body and closer to the actin filaments [14], also increasing its sensitivity to Ca 2+ , which facilitate interactions within the sarcomeric apparatus [15]. Another consistent theory considers that preconditioning activities are responsible for increasing transmittance of excitation potentials in the synaptic junction and spinal cord levels [16– 18]. "
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    ABSTRACT: Postactivation potentiation (PAP) is known to enhance force production. Maximal isometric strength assessment protocols usually consist of two or more maximal voluntary isometric contractions (MVCs). The objective of this study was to determine if PAP would influence isometric strength assessment. Healthy male volunteers (n = 23) performed two five-second MVCs separated by a 180-seconds interval. Changes in isometric peak torque (IPT), time to achieve it (tPTI), contractile impulse (CI), root mean square of the electromyographic signal during PTI (RMS), and rate of torque development (RTD), in different intervals, were measured. Significant increases in IPT (240.6 ± 55.7 N·m versus 248.9 ± 55.1 N·m), RTD (746 ± 152 N·m·s(-1) versus 727 ± 158 N·m·s(-1)), and RMS (59.1 ± 12.2% RMSMAX versus 54.8 ± 9.4% RMSMAX) were found on the second MVC. tPTI decreased significantly on the second MVC (2373 ± 1200 ms versus 2784 ± 1226 ms). We conclude that a first MVC leads to PAP that elicits significant enhancements in strength-related variables of a second MVC performed 180 seconds later. If disconsidered, this phenomenon might bias maximal isometric strength assessment, overestimating some of these variables.
    Full-text · Article · Jul 2014 · BioMed Research International
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    • "HCM is the most common cause of SCD among young individuals and competitive athletes [12]. Recent genetic studies have revealed that mutations in MYL2 are more common than previously reported (for review see [13] [14]) and in just the past few years, new MYL2 mutations have been identified [15] [16], with some detected multiple times and in different ethnic populations (Fig. 1A) [17] [18]. This report focuses on the Lysine 104 → Glutamic acid mutation in MYL2 (Lys104Glu) identified in a Danish family, with the proband diagnosed with HCM at the age of 17 years [18] [19]. "
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    ABSTRACT: We have examined, for the first time, the effects of the familial hypertrophic cardiomyopathy (HCM)- associated Lys104Glu mutation in the myosin regulatory light chain (RLC). Transgenic mice expressing the Lys104Glu substitution (Tg-MUT) were generated and the results compared to Tg-WT (wild-type human ventricular RLC) mice. Echocardiography with pulse wave Doppler in 6month-old Tg-MUT showed early signs of diastolic disturbance with significantly reduced E/A transmitral velocities ratio. Invasive hemodynamics in 6month-old Tg-MUT mice also demonstrated a borderline significant prolonged isovolumic relaxation time (Tau) and a tendency for slower rate of pressure decline, suggesting alterations in diastolic function in Tg-MUT. Six month-old mutant animals had no LV hypertrophy; however, at >13months they displayed significant hypertrophy and fibrosis. In skinned papillary muscles from 5-6 month-old mice a mutation induced reduction in maximal tension and slower muscle relaxation rates were observed. Mutated cross-bridges showed increased rates of binding to the thin filaments and a faster rate of the power stroke. In addition, ~2-fold lower level of RLC phosphorylation was observed in the mutant compared to Tg-WT. In line with the higher mitochondrial content seen in Tg-MUT hearts, the MUT-myosin ATPase activity was significantly higher than WT-myosin, indicating increased energy consumption. In the in vitro motility assay, MUT-myosin produced higher actin sliding velocity under zero load, but the velocity drastically decreased with applied load in the MUT vs. WT myosin. Our results suggest that diastolic disturbance (impaired muscle relaxation, lower E/A) and inefficiency of energy use (reduced contractile force and faster ATP consumption) may underlie the Lys104Glu-mediated HCM phenotype.
    Full-text · Article · Jun 2014 · Journal of Molecular and Cellular Cardiology
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    • "The phenomenon of PAP may be explained by changes that occur on muscular level and more particularly by the phosphorylation of myosin regulatory light-chains. The myosin molecule consists of six subunits, two heavy and four light chains (Szczesna, 2003). Each heavy chain contains the head and a tail and each pair of light chain consists of an essential light chain and a regulatory light chain. "
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    ABSTRACT: The responsible mechanisms for post-activation potentiation have been a popular research issue during the past years. One commonly mentioned mechanism is the force enhancement via phosphorylation of myosin regulatory light chains, which affects the sensitivity of the actin - myosin to Ca2+. An alternative factor that could contribute or affect post-activation potentiation could be of neural nature. The increase in motor neuron excitability and the recruitment of more motor units could lead to higher rate of force development. H-reflex has been used to investigate possible neural adaptations during post activation potentiation. Methodological considerations and conflicting results have appeared due to different applied methods, which are discussed. Clearly, there is a need for further studies to support or reject the hypothesis of neural contribution to the occurrence of post-activation potentiation phenomenon.
    Full-text · Article · Jun 2014
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