Developmental changes in rat cardiac titin/connectin: transitions in normal animals and in mutants with a delayed pattern of isoform transition

Greaser, Marion L.; Krzesinski, Paul R.; Warren, Chad M.; Kirkpatrick, Brian; Campbell, Kenneth S.; Moss, Richard L.

doi:10.1007/s10974-005-9039-0

Cited by 63 publications

(91 citation statements)

References 44 publications

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“…These were gradually replaced by adult forms (N2BA-A1, N2BA-A2) with sizes of 3390 kDa and 3220 kDa, respectively (Warren et al 2004). Similar titin isoform transformations were observed in embryonic/neonatal hearts of rat and other mammals and reported by the researchers (Lahmers et al 2004;Opitz et al 2004;Greaser et al 2005;Krüger et al 2006).…”

Section: Electrophoretic Detection Of Titin Isoformssupporting

confidence: 78%

Nuances of electrophoresis study of titin/connectin

Vikhlyantsev

Podlubnaya

2017

Biophys Rev

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Almost 40 years has passed since the discovery of giant elastic protein titin (also known as connectin) of striated and smooth muscles using gel electrophoresis. Sodium dodecyl sulfate polyacrylamide gel electrophoresis is a major technique for studying the isoform composition and content of titin. This review provides historical insights into the technical aspects of the electrophoresis methods used to identify titin and its isoforms. We particularly focus on the nuances of the technique that improve the preservation of its primary structure so that its high molecular weight isoforms can be visualized.

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Section: Electrophoretic Detection Of Titin Isoformssupporting

confidence: 78%

Nuances of electrophoresis study of titin/connectin

Vikhlyantsev

Podlubnaya

2017

Biophys Rev

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“…A few rats from this study, however, had ventricle titin patterns inconsistent with their ages, and their profiles appeared similar to those from much younger animals [25]. All the animals with the altered profiles were from the same litter, and this immediately suggested there was a genetic factor involved.…”

Section: Genetics and Isoform Patternsmentioning

confidence: 56%

“…Factors for determining titin isoform expression are currently unknown. However, an initial description of a strain of rats that showed altered titin isoform expression due to an apparent mutation was previously reported by our group [25]. The current paper provides detailed characterization of this novel rat genetic model and provides strong evidence that titin normally functions to prevent overstretch of the sarcomere.…”

Section: Introductionmentioning

confidence: 62%

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Mutation that dramatically alters rat titin isoform expression and cardiomyocyte passive tension

Greaser

Warren

Esbona

et al. 2008

Journal of Molecular and Cellular Cardiology

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102

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Titin is a very large alternatively spliced protein that performs multiple functions in heart and skeletal muscle. A rat strain is described with an autosomal dominant mutation that alters the isoform expression of titin. While wild type animals go through a developmental program where the 3.0 MDalton N2B becomes the major isoform expressed by two to three weeks after birth (~85%), the appearance of the N2B is markedly delayed in heterozygotes and never reaches more than 50% of the titin in the adult. Homozygote mutants express a giant titin of the N2BA isoform type (3.9 MDalton) that persists as the primary titin species through ages of more than one and half years. The mutation does not affect the isoform switching of troponin T, a protein that also is alternatively spliced with developmental changes. The basis for the apparently greater size of the giant titin in homozygous mutants was not determined, but additional length was not due to inclusion of sequence from larger numbers of PEVK exons or the Novex III exon. Passive tension measurements using isolated cardiomyocytes from homozygous mutants showed that cells could be stretched to sarcomere lengths greater than 4 µm without breakage. This novel rat model should be useful for exploring the potential role of titin in the Frank-Starling relationship and mechano-sensing/signaling mechanisms.

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“…In this current issue, Dr. Greaser and his co-workers introduce a novel and rather unusual tool to the arsenal of investigative tools for the study of titin physiology [14]. Rather than attempting to genetically alter titin expression in transgenic mice, these investigators have cleverly capitalized on an apparent spontaneous titin mutation which they serendipitously discovered in a litter of Sprague-Dawley rats during the course of a study on the alternative splicing of titin during development [15]. As mentioned above, the expressed isoform of titin generally becomes shorter with ageing, and this also occurs in the rat [2,3].…”

mentioning

confidence: 99%

Some rat: A very special rat with a rather special titin

Cazorla¹,

Tombe²

2008

Journal of Molecular and Cellular Cardiology

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Cycling cross-bridges, the molecular interactions between the contractile proteins actin and myosin, generate the muscle force that underlies cardiac pressure development. In striated muscle, these proteins are organized in the thick and thin filaments that together form the sarcomere. A more recent discovery localizes a third filament to the sarcomere, one that is composed of titin. Titin, also known as connectin, is a giant protein (3-4 MDaltons) that is an abundant protein in striated muscle forming up to 10% of the total protein content of the cardiac cell. Titin extends half the length of the sarcomere from the Z-disc through the I-band and Aband on to the M-line (~1 μm). The molecule is tightly anchored at its NH 2 -terminus in the Zdisk via interactions with alpha-actinin and at its C-terminal domain to the M-line via interactions with myosin. The cell biology of titin has been the subject of intense study by several groups following its discovery in 1979 [1]. was immediately recognized that a significant function of titin in the sarcomere might be structural. Indeed, titin has emerged as the main cellular structure responsible for passive striated muscle cell stiffness [2,3]. Furthermore, within the physiological range of cardiac volume, titin appears to be responsible for a significant portion of the diastolic passive filling pressure of the heart; the remainder of the elastic force being generated by extracellular matrix collagen [4]. The elasticity of titin originates within the I-band portion due to the presence of i) tandem immunoglobulin (Ig) repeats, ii) a region rich in proline (P), glutamate (E), valine (V), and lysine (K), the PEVK region and iii) a region with a sequence unique to cardiac titin, the N2B region. Alternative splicing provides additional tandem Ig repeats that insert between the N2B and PEVK regions. These longer titin isoforms also have an N2A region and are termed N2BA. In a sarcomere at slack length, titin is highly folded with many of the regions acting as entropic springs. As the sarcomere is stretched, the links between the tandem Ig repeats extend first. As the stretch proceeds, the PEVK sequence unfolds and at the upper end of the physiological range of sarcomere lengths the N2B region also unfolds. Over the normal physiological range of sarcomere lengths and forces, the tandem Ig repeats are not thought to unfold, although these repeats can be made to unfold in isolated titin molecules [2,3].It has become increasingly clear recently that titin's functions are far more complex and that this giant molecule may play a much larger role in striated muscle physiology than merely as a passive stress bearing protein. For example, it has been suggested that titin plays an important

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Developmental changes in rat cardiac titin/connectin: transitions in normal animals and in mutants with a delayed pattern of isoform transition

Cited by 63 publications

References 44 publications

Nuances of electrophoresis study of titin/connectin

Nuances of electrophoresis study of titin/connectin

Mutation that dramatically alters rat titin isoform expression and cardiomyocyte passive tension

Some rat: A very special rat with a rather special titin

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