Molecular Basis for the Influence of Muscle Length on Myocardial Performance

Babu, A.; Sonnenblick, Edmund H.; Gulati, Jagdish

doi:10.1126/science.3353709

Cited by 130 publications

(73 citation statements)

References 23 publications

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“…Each transfection was repeated at least three times. display important functional differences (2,31). Structurally, the two genes-share a high degree of amino acid sequence identity and identical intron-exon boundaries with the exception of exon 1 and the 5' flanking regions, which are distinct (12,32,33,37).…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of a cardiac-specific transcriptional regulatory element in the slow/cardiac troponin C gene.

Parmacek¹,

Vora²,

Shen³

et al. 1992

Mol. Cell. Biol.

119

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The slow/cardiac troponin C (cTnC) gene has been used as a model system for defining the molecular mechanisms that regulate cardiac and skeletal muscle-specific gene expression during mammalian development. cTnC is expressed continuously in both embryonic and adult cardiac myocytes but is expressed only transiently in embryonic fast skeletal myotubes. We have reported previously that cTnC gene expression in skeletal myotubes is controlled by a developmentally regulated, skeletal muscle-specific transcriptional enhancer located within the first intron of the gene (bp 997 to 1141). In this report, we show that cTnC gene expression in cardiac myocytes both in vitro and in vivo is regulated by a distinct and independent transcriptional promoter and enhancer located within the immediate 5' flanking region of the gene (bp -124 to +32). DNase I footprint and electrophoretic mobility shift assay analyses demonstrated that this cardiac-specific promoter/enhancer contains five nuclear protein binding sites (designated CEF1, CEF-2, and CPF1-3), four of which bind novel cardiac-specific nuclear protein complexes. Functional analysis of the cardiac-specific cTnC enhancer revealed that mutation of either the CEF-1 or CEF-2 nuclear protein binding site abolished the activity of the cTnC enhancer in cardiac myocytes. Taken together, these results define a novel mechanism for developmentally regulating a single gene in multiple muscle cell lineages. In addition, they identify previously undefined cardiac-specific transcriptional regulatory motifs and trans-acting factors.

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Section: Discussionmentioning

confidence: 99%

Identification and characterization of a cardiac-specific transcriptional regulatory element in the slow/cardiac troponin C gene.

Parmacek¹,

Vora²,

Shen³

et al. 1992

Mol. Cell. Biol.

119

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“…The mechanisms responsible are still debated, with evidence suggesting roles for Troponin C (Babu et al, 1988; but see , Troponin I (Arteaga et al, 2000), Titin (Fukuda et al, 2001;Fukuda et al, 2003;Terui et al, 2008), and lateral/radial spacing of the thick and thin filaments Williams et al, 2013).…”

Section: Fig 7 Predicted Muscle Lengthsmentioning

confidence: 99%

The length-force behavior and operating length range of squid muscle varies as a function of position in the mantle wall

Thompson

Shelton

Kier

2014

Journal of Experimental Biology

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Hollow cylindrical muscular organs are widespread in animals and are effective in providing support for locomotion and movement, yet are subject to significant non-uniformities in circumferential muscle strain. During contraction of the mantle of squid, the circular muscle fibers along the inner (lumen) surface of the mantle experience circumferential strains 1.3 to 1.6 times greater than fibers along the outer surface of the mantle. This transmural gradient of strain may require the circular muscle fibers near the inner and outer surfaces of the mantle to operate in different regions of the length-tension curve during a given mantle contraction cycle. We tested the hypothesis that circular muscle contractile properties vary transmurally in the mantle of the Atlantic longfin squid, Doryteuthis pealeii. We found that both the length-twitch force and length-tetanic force relationships of the obliquely striated, central mitochondria-poor (CMP) circular muscle fibers varied with radial position in the mantle wall. CMP circular fibers near the inner surface of the mantle produced higher force relative to maximum isometric tetanic force, P 0 , at all points along the ascending limb of the length-tension curve than CMP circular fibers near the outer surface of the mantle. The mean ± s.d. maximum isometric tetanic stresses at L 0 (the preparation length that produced the maximum isometric tetanic force) of 212±105 and 290±166 kN m −2 for the fibers from the outer and inner surfaces of the mantle, respectively, did not differ significantly (P=0.29). The mean twitch:tetanus ratios for the outer and inner preparations, 0.60±0.085 and 0.58±0.10, respectively, did not differ significantly (P=0.67). The circular fibers did not exhibit length-dependent changes in contraction kinetics when given a twitch stimulus. As the stimulation frequency increased, L 0 was approximately 1.06 times longer than L TW , the mean preparation length that yielded maximum isometric twitch force. Sonomicrometry experiments revealed that the CMP circular muscle fibers operated in vivo primarily along the ascending limb of the length-tension curve. The CMP fibers functioned routinely over muscle lengths at which force output ranged from only 85% to 40% of P 0 , and during escape jets from 100% to 30% of P 0 . Our work shows that the functional diversity of obliquely striated muscles is much greater than previously recognized.

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“…To answer this question, different lines of investigation and hypotheses are presently under investigation. Some authors suggest that TnC itself might be the sensor of changes in muscle length [20][21][22] . This hypothesis is based on molecular differences between TnC of cardiac and skeletal muscle, which might be associated with the difference in the force-length relationship in both muscles.…”

Section: The Degree Of Activation Of Cardiac Muscle Depends On Musclementioning

confidence: 99%

The degree of activation of cardiac muscle depends on muscle length

Rassier¹

2000

Arq. Bras. Cardiol.

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The Frank-Starling mechanism of the heart 1-3 can be described as the relationship between force and length of cardiac muscle. With the advent of the cross bridge theory of muscle contraction 4,5 and Gordon and collaborator's classical study 6 describing the fitting of this theory to the force-length relationship in skeletal muscle, several investigators started to study this relationship in cardiac muscle.The force-length relation in cardiac muscle is observed in a small variety of sarcomere lengths, between approximately 1.8 µm and 2.3 µm. This region corresponds to the ascending limb of the force-length relation of skeletal-muscle 6 . The force levels of the myocardium vary from zero at 1.8 µm to maximal force values at 2.3 µm. This large variation in force results in a very sleep force-length relation, especially when compared with this relation in skeletal muscle ( fig. 1). To get an idea, when the tension developed by the myocardium at different sarcomere lengths is normalized in relation to its maximal force (F max ) at the point where maximal length (L max ) occurs, the developed tension is approximately 10-15% when the myocardium is measured at 80% L max . Yet in skeletal muscle, normalized force is approximately 80-85% of F max 7 under the same conditions ( fig.1).This difference between skeletal and cardiac muscle shows that the force-length relationship in the myocardium are not a simple function of the degree of superposition of actin and myosin filaments. Because their lengths are similar in both muscles, other factors must be involved in the muscle force-length relationship. During recent years, this difference has been attributed to the dependence of muscle activation on sarcomere length 8 .Muscle activation has been used collectively in the literature to refer to various processes able to initiate muscle contraction, modifying the muscle state from "inactive" to "active". Thus, muscle activation has been associated with the frequency of muscle stimulation or membrane action potentials with intracellular Ca 2+ concentration [Ca 2+ ] i , or the occupation of the protein troponin C (TnC) by Ca 2+ . In this article, the term muscle contraction will be utilized to describe the proportion of TnC associated with Ca 2+ . The association TnC/Ca 2+ represents a fundamental event in muscle contraction; therefore, the sensitivity of TnC to Ca 2+ will be discussed in greater detail. This choice, furthermore, comes from studies shewing that myocardial force changes due to muscle length are unrelated to [Ca 2+ ] i 9,10 . The present article contains a review of studies related to the dependence of force and, more importantly, of the process of myocardial muscle activation on muscle length. In particular, the article intends to investigate mechanisms responsible for the dependence of the sensitivity of filaments to Ca 2+ on muscle length, as proposed in the literature.Dependence of the sensitivity of filaments to Ca 2+ on muscle length -Evidence that the activation of the myocardium is dependent on muscle lengt...

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Molecular Basis for the Influence of Muscle Length on Myocardial Performance

Cited by 130 publications

References 23 publications

Identification and characterization of a cardiac-specific transcriptional regulatory element in the slow/cardiac troponin C gene.

Identification and characterization of a cardiac-specific transcriptional regulatory element in the slow/cardiac troponin C gene.

The length-force behavior and operating length range of squid muscle varies as a function of position in the mantle wall

The degree of activation of cardiac muscle depends on muscle length

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