Role of the Fetal and α/β Exons in the Function of Fast Skeletal Troponin T Isoforms: Correlation with Altered Ca2+ Regulation Associated with Development

Chaudhuri, Tathagata; Mukherjea, Monalisa; Sachdev, Sanjay; Randall, Jeffrey; Sarkar, Satyapriya

doi:10.1016/j.jmb.2005.06.066

Cited by 21 publications

(17 citation statements)

References 74 publications

(151 reference statements)

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“…Interestingly, this isoform is characterized by an increased number of glutamic acid residues in the variable region at the NH 2 terminus and an increased number of polar amino acids in the COOH terminus region. As it is known that fTnT isoforms finely regulate the affinity of the ternary troponin complex for calcium and, ultimately, the contraction capability of the sarcomeric unit following calcium stimulation (31), we speculate that these changes may influence the assembly of the ternary troponin complex and/or finely tune its interactions with other myofibrillar proteins, such as tropomyosin, providing novel characteristics to the contractile unit (4,46,47).…”

Section: Discussionmentioning

confidence: 95%

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

Sancisi

Germinario

Esposito

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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cioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is characterized by atrophy and weakness of selective muscle groups. FSHD is considered an autosomal dominant disease with incomplete penetrance and unpredictable variability of clinical expression within families. Mice overexpressing FRG1 (FSHD region gene 1), a candidate gene for this disease, develop a progressive myopathy with features of the human disorder. Here, we show that in FRG1-overexpressing mice, fast muscles, which are the most affected by the dystrophic process, display anomalous fast skeletal troponin T (fTnT) isoform, resulting from the aberrant splicing of the Tnnt3 mRNA that precedes the appearance of dystrophic signs. We determine that muscles of FRG1 mice develop less strength due to impaired contractile properties of fast-twitch fibers associated with an anomalous MyHC-actin ratio and a reduced sensitivity to Ca 2ϩ . We demonstrate that the decrease of Ca 2ϩ sensitivity of fast-twitch fibers depends on the anomalous troponin complex and can be rescued by the substitution with the wild-type proteins. Finally, we find that the presence of aberrant splicing isoforms of TNNT3 characterizes dystrophic muscles in FSHD patients. Collectively, our results suggest that anomalous TNNT3 profile correlates with the muscle impairment in both humans and mice. On the basis of these results, we propose that aberrant fTnT represents a biological marker of muscle phenotype severity and disease progression. muscular dystrophy; aberrant splicing; muscle weakness; FRG1; troponin T FACIOSCAPULOHUMERAL MUSCULAR dystrophy (FSHD), one of the three most common hereditary myopathies, presents progressive atrophy and weakness of a highly specific set of muscle groups (10,11,31). FSHD is characterized by insidious onset and unpredictable progression with high variability of clinical expression, even within the same family (36,37,42). At present, no molecular mechanisms have been implicated in the development of these disease phenotypes, and no biological markers are available to define and monitor disease expression.More than 50 genes have been associated with muscular dystrophies (MD), whose genetic defects have been molecularly defined, and numerous animal models have been developed (30). In many cases, invaluable insights into disease mechanisms, structure and function of gene products, and approaches for therapeutic interventions have benefited from the study of animal models of the different MDs (1). In this context, FSHD is unique because no mutations have been found in any protein-coding gene. Instead, FSHD has been associated with reduction of the number of tandemly repeated 3.3-kb DNA segments (named D4Z4 repeats) located at the subtelomeric region of chromosome 4q (2, 44, 48). The number of D4Z4 repeats varies from 11 to 150 in the general population, whereas less than 11 repeats are present in sporadic and familial FSHD patients (48). The current model to explain FSHD is that the reduction of D4Z4 repeats in FSHD subjects initiates in...

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Section: Discussionmentioning

confidence: 95%

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

Sancisi

Germinario

Esposito

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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“…While some alternative splicing events are thought to result from stochastic variation in spliceosome binding [37], there is evidence for differential distribution of alternatively spliced genes among different tissues, with the highest prevalence reported in the functionally complex brain, testis, and liver [35,39]. Furthermore, several cases where alternative splicing is tightly regulated are known, including a-tropomyosin [40], troponin T [41], and PTCH1 oncogene [42].…”

Section: Atypical Splicing Of Existing Genesmentioning

confidence: 99%

Current topics in genome evolution: Molecular mechanisms of new gene formation

Babushok

Ostertag

Kazazian

2006

Cell. Mol. Life Sci.

124

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Comparative genome analyses reveal that most functional domains of human genes have homologs in widely divergent species. These shared functional domains, however, are differentially shuffled among evolutionary lineages to produce an increasing number of domain architectures. Combined with duplication and adaptive evolution, domain shuffling is responsible for the great phenotypic complexity of higher eukaryotes. Although the domain-shuffling hypothesis is generally accepted, determining the molecular mechanisms that lead to domain shuffling and novel gene creation has been challenging, as sequence features accompanying the formation of known genes have been obscured by accumulated mutations. The growing availability of genome sequences and EST databases allows us to study the characteristics of newly emerged genes. Here we review recent genome-wide DNA and EST analyses, and discuss the three major molecular mechanisms of gene formation: (1) atypical spicing, both within and between genes, followed by adaptation, (2) tandem and interspersed segmental duplications, and (3) retrotransposition events.

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“…The pre-mRNAs for all three genes are alternatively spliced, leading to the production of mRNAs encoding multiple protein variants that exhibit differential functional characteristics. Consequently, changes in the pattern of troponin T pre-mRNA alternative splicing results in variations in muscle force, power output, and calcium sensitivity in both insects (Fitzhugh et al 1997; Marden et al 2001; Schilder et al 2007) and mammals (Pan et al 1992; Briggs et al 1996; Chaudhuri et al 2005; Sancisi et al 2014). Although little is known about mechanisms involved in regulating alternative splicing of the troponin T pre-mRNA in general, the pattern of rodent Tnnt3 splice variant expression is rapidly altered in young rats in response to changes in effective body mass, e.g.…”

Section: Introductionmentioning

confidence: 99%

Influence of ageing and essential amino acids on quantitative patterns of troponin T alternative splicing in human skeletal muscle

Coble

Schilder

Berg

et al. 2015

Appl. Physiol. Nutr. Metab.

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Ageing is associated with a loss of skeletal muscle performance, a condition referred to as sarcopenia. In part, the age-related reduction in performance is due to a selective loss in muscle fiber mass, but mass-independent effects have also been demonstrated. An important mass-independent determinant of muscle performance is the pattern of expression of isoforms of proteins that participate in muscle contraction, e.g. the troponins. In the present study we tested the hypothesis that ageing impairs alternative splicing of the pre-mRNA encoding fast troponin T (Tnnt3) in human vastus lateralis muscle. Furthermore, we hypothesized that resistance exercise alone or in combination with consumption of essential amino acids will attenuate age-associated effects on Tnnt3 alternative splicing. Our results indicate that ageing negatively affects the pattern of Tnnt3 pre-mRNA alternative splicing in a manner that correlates quantitatively with age-associated reductions in muscle performance. Interestingly, whereas vastus lateralis Tnnt3 alternative splicing was unaffected by a bout of resistance exercise 24 hour prior to muscle biopsy, ingestion of a mixture of essential amino acids after resistance exercise resulted in a significant shift in the pattern of Tnnt3 spliceform expression in both age groups to one predicted to promote greater muscle performance. We conclude that essential amino acid supplementation after resistance exercise may provide a means to reduce impairments in skeletal muscle quality during ageing in humans.

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Role of the Fetal and α/β Exons in the Function of Fast Skeletal Troponin T Isoforms: Correlation with Altered Ca2+ Regulation Associated with Development

Cited by 21 publications

References 74 publications

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

Current topics in genome evolution: Molecular mechanisms of new gene formation

Influence of ageing and essential amino acids on quantitative patterns of troponin T alternative splicing in human skeletal muscle

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