Titin and Diaphragm Dysfunction in Chronic Obstructive Pulmonary Disease

Ottenheijm, Coen A.C.; Heunks, Leo; Hafmans, T.G.M.; Ven, Peter F.M. van der; Benoist, Caroline; Zhou, Honghui; Labeit, Siegfried; Granzier, Henk; Dekhuijzen, P.N.R.

doi:10.1164/rccm.200507-1056oc

Cited by 72 publications

(90 citation statements)

References 34 publications

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“…It should be borne in mind, however, that tumor lines are overrepresented in cDNA libraries: 26% of the cDNA libraries annotated in the eVOC pathology annotation (40) are annotated as ''normal,'' whereas 49% are annotated as ''tumor.'' There has been abundant recent work associating alternative splicing with stresses incurred by cancer and other disorders (41)(42)(43), although in many cases the increase in expression of the aberrant variant may be a side effect of the general breakdown of cellular function rather than part of the instigation process. Indeed the importance of alternative splicing in cancer is such that diagnosis can now be carried out by using isoform-sensitive microarrays based on splice isoform profiles (44).…”

Section: Resultsmentioning

confidence: 99%

The implications of alternative splicing in the ENCODE protein complement

Tress

Martelli

Frankish

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

199

187

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Alternative premessenger RNA splicing enables genes to generate more than one gene product. Splicing events that occur within protein coding regions have the potential to alter the biological function of the expressed protein and even to create new protein functions. Alternative splicing has been suggested as one explanation for the discrepancy between the number of human genes and functional complexity. Here, we carry out a detailed study of the alternatively spliced gene products annotated in the ENCODE pilot project. We find that alternative splicing in human genes is more frequent than has commonly been suggested, and we demonstrate that many of the potential alternative gene products will have markedly different structure and function from their constitutively spliced counterparts. For the vast majority of these alternative isoforms, little evidence exists to suggest they have a role as functional proteins, and it seems unlikely that the spectrum of conventional enzymatic or structural functions can be substantially extended through alternative splicing.function ͉ human ͉ isoforms ͉ splice ͉ structure A lternative mRNA splicing, the generation of a diverse range of mature RNAs, has considerable potential to expand the cellular protein repertoire (1-3), and recent studies have estimated that 40-80% of multiexon human genes can produce differently spliced mRNAs (4, 5). The importance of alternative splicing in processes such as development (6) has long been recognized, and proteins coded by alternatively spliced transcripts have been implicated in a number of cellular pathways (7-9). The extent of alternative splicing in eukaryotic genomes has lead to suggestions that alternative splicing is key to understanding how human complexity can be encoded by so few genes (10).The pilot project of the Encyclopedia of DNA Elements (ENCODE) (11), which aims to identify all the functional elements in the human genome, has undertaken a comprehensive analysis of 44 selected regions that make up 1% of the human genome. One valuable element of the project has been the detailing of a reference set of manually annotated splice variants by the GENCODE consortium (12). The annotation by the GENCODE consortium is an extension of the manually curated annotation by the Havana team at The Sanger Institute.Although a full understanding of the functional implications of alternative splicing is still a long way off, the GENCODE set has provided us with the material to make an in-depth assessment of a systematically collected reference set of splice variants. ResultsAlternative Splicing Frequency. The GENCODE set is made up of 2,608 annotated transcripts for 487 distinct loci. A total of 1,097 transcripts from 434 loci are predicted to be protein coding. There are on average 2.53 protein coding variants per locus; 182 loci have only one variant, whereas one locus, RP1-309K20.2 (CPNE1) has 17 coding variants.A total of 57.8% of the loci are annotated with alternatively spliced transcripts, although there are differences between target re...

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Section: Resultsmentioning

confidence: 99%

The implications of alternative splicing in the ENCODE protein complement

Tress

Martelli

Frankish

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

199

187

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“…It has been proposed that the adaptations of the diaphragm in COPD demonstrate a kind of muscle dysfunction or impairment (62)(63)(64)84). This may be true, and findings such as loss of Ca 2ϩ sensitivity and atrophy certainly lead us in this direction.…”

Section: Discussionmentioning

confidence: 99%

“…Ottenheijm et al (63) have also observed reductions in the expression levels of the protein nebulin in patients with COPD. Nebulin is another large cytoskeleton protein, the function of which is still speculative (53) but may be involved, not only in cytoskeleton structure, but also in Ca 2ϩ regulation (61).…”

Section: Alterations In the Passive Mechanical Properties Of Respiratmentioning

confidence: 94%

“…In permeabilized human diaphragm fibers from biopsy specimens, there is a decrease in the overall elastic "restoring force" (55), as shown in Fig. 3A, or the passive tension of single-fiber segments as they respond to lengthening (63). This reduction in the parallel elastic behavior of single fibers is largely attributed to the properties of the protein, titin, a large, unfolding macromolecule that spans the distance between Z disk and the M region within the sarcomere.…”

Section: Alterations In the Passive Mechanical Properties Of Respiratmentioning

confidence: 97%

“…One of the more interesting recent observations in the human diaphragm from emphysema patients relates to the alterations seen in passive mechanical characteristics (55,63). In animal models of elastase emphysema, there is currently no evidence for substantial changes in the passive elastic properties of whole, intact muscle, when normalized to sarcomere length (85).…”

Section: Alterations In the Passive Mechanical Properties Of Respiratmentioning

confidence: 99%

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Respiratory muscle fiber remodeling in chronic hyperinflation: dysfunction or adaptation?

Clanton¹,

Levine²

2009

Journal of Applied Physiology

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Clanton TL, Levine S. Respiratory muscle fiber remodeling in chronic hyperinflation: dysfunction or adaptation? J Appl Physiol 107: 324 -335, 2009. First published April 9, 2009 doi:10.1152/japplphysiol.00173.2009.-The diaphragm and other respiratory muscles undergo extensive remodeling in both animal models of emphysema and in human chronic obstructive pulmonary disease, but the nature of the remodeling is different in many respects. One common feature is a shift toward improved endurance characteristics and increased oxidative capacity. Furthermore, both animals and humans respond to chronic hyperinflation by diaphragm shortening. Although in rodent models this clearly arises by deletion of sarcomeres in series, the mechanism has not been proven conclusively in human chronic obstructive pulmonary disease. Unique characteristics of the adaptation in human diaphragms include shifts to more predominant slow, type I fibers, expressing slower myosin heavy chain isoforms, and type I and type II fiber atrophy. Although some laboratories report reductions in specific force, this may be accounted for by decreases in myosin heavy chain content as the muscles become more oxidative and more efficient. More recent findings have reported reductions in Ca 2ϩ sensitivity and reduced myofibrillar elastic recoil. In contrast, in rodent models of disease, there is no consistent evidence for loss of specific force, no consistent shift in fiber populations, and atrophy is predominantly seen only in fast, type IIX fibers. This review challenges the hypothesis that the adaptations in human diaphragm represent a form of dysfunction, secondary to systemic disease, and suggest that most findings can as well be attributed to adaptive processes of a complex muscle responding to unique alterations in its working environment. diaphragm; fiber type; sarcomere; skeletal muscle; emphysema THIS REVIEW IS INTENDED TO bring readers up to date with accumulating evidence that the diaphragm undergoes remarkable adaptations to chronic hyperinflation and chronic lung obstruction. Some of these adaptations are expected, based on well known responses of limb muscle to chronic changes in length and mechanical load, but others appear to be surprisingly unique, revealing aspects of muscle plasticity and pathology that are not anticipated from known basic science concepts. We will concentrate this review on what has been observed, primarily at the muscle fiber level in both animals and humans, with primary emphasis on the diaphragm. There have been several excellent previous reviews of this area, and the reader is encouraged to refer to these (13,41,58,65,66). Where possible, we will attempt to complement, update, and at times challenge current concepts with the purpose of furthering dialogue and promoting further inquiry. LENGTH PLASTICITYThe diaphragm, like all other muscles, exhibits a characteristic length-tension relationship analogous to the Frank-Starling curve for the heart. As length is increased in the relaxed muscle, a passive length-tension cu...

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Factors Limiting Exercise Tolerance in Chronic Lung Diseases

Vogiatzis

Zakynthinos

2012

Comprehensive Physiology

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The major limitation to exercise performance in patients with chronic lung diseases is an issue of great importance since identifying the factors that prevent these patients from carrying out activities of daily living provides an important perspective for the choice of the appropriate therapeutic strategy. The factors that limit exercise capacity may be different in patients with different disease entities (i.e., chronic obstructive, restrictive or pulmonary vascular lung disease) or disease severity and ultimately depend on the degree of malfunction or miss coordination between the different physiological systems (i.e., respiratory, cardiovascular and peripheral muscles). This review focuses on patients with chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and pulmonary vascular disease (PVD). ILD and PVD are included because there is sufficient experimental evidence for the factors that limit exercise capacity and because these disorders are representative of restrictive and pulmonary vascular disorders, respectively. A great deal of emphasis is given, however, to causes of exercise intolerance in COPD mainly because of the plethora of research findings that have been published in this area and also because exercise intolerance in COPD has been used as a model for understanding the interactions of different pathophysiologic mechanisms in exercise limitation. As exercise intolerance in COPD is recognized as being multifactorial, the impacts of the following factors on patients' exercise capacity are explored from an integrative physiological perspective: (i) imbalance between the ventilatory capacity and requirement; (ii) imbalance between energy demands and supplies to working respiratory and peripheral muscles; and (iii) peripheral muscle intrinsic dysfunction/weakness.

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Titin and Diaphragm Dysfunction in Chronic Obstructive Pulmonary Disease

Cited by 72 publications

References 34 publications

The implications of alternative splicing in the ENCODE protein complement

The implications of alternative splicing in the ENCODE protein complement

Respiratory muscle fiber remodeling in chronic hyperinflation: dysfunction or adaptation?

Factors Limiting Exercise Tolerance in Chronic Lung Diseases

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