Restrictive cardiomyopathy mutations demonstrate functions of the C-terminal end-segment of troponin I

Akhter, Shirin; Bueltmann, Kenneth W.; Huang, Xupei; Jin, Jian‐Ping

doi:10.1016/j.abb.2013.12.001

Cited by 15 publications

(17 citation statements)

References 43 publications

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“…Calcium pCa curve measurement data indicated a significant curve left-shift in myofibers from the RCM cTnI 193His mice, indicating an increase of myofibril sensitivity to Ca 2+ [10]. The data obtained from Ca 2+ transient measurements and biochemical assays indicated that cTnI mutation caused myofibril Ca 2+ hypersensitivity was a key factor resulting in a delayed calcium drop-off from the myofilaments and a delayed relaxation time [10,12].…”

Section: Cellular and Molecular Mechanisms Of Rcm Ctni Mutationsmentioning

confidence: 93%

Troponin Mutation Caused Diastolic Dysfunction and Experimental Treatment in Transgenic Mice with Cardiomyopathy

Xu¹,

Tian²,

Huang³

2014

JAMR

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Abstract-Troponin, a contractile protein of the thin filament of striated muscle, consists of three subunits: troponin C (TnC), troponin T (TnT), and troponin I (TnI). Cardiac troponin I (cTnI) plays a critical role in regulation of cardiac function. The physiological effect of cTnI, as an inhibitory subunit of troponin complex, is to prevent the interaction between myosin heavy chain heads and actins, i.e. the cross-bridge formation, and to ensure a proper relaxation of cardiac myofilaments. In pathological conditions, the deficiency of cTnI or mutations in cTnI especially in the C-terminus of cTnI is associated with diastolic dysfunction caused by myofibril hypersensitivity to Ca 2+ . Our laboratory has generated cTnI knockout mouse model to investigate the cellular and molecular function of cTnI and created cTnI mutant disease mouse models to explore the pathophysiology caused by cTnI mutations in the heart. Here, we present our recent studies on physiological function of cTnI in the heart and the pathological consequences caused by the cTnI mutations in the diseased heart using the transgenic mouse models. The mechanisms underlying diastolic dysfunction and heart failure caused by cTnI mutations are explored in cell-based assays and in transgenic animal models. These studies provide us with useful information in searching for therapeutic strategies and target-oriented medication for the treatment of diastolic dysfunction and heart failure.

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Section: Cellular and Molecular Mechanisms Of Rcm Ctni Mutationsmentioning

confidence: 93%

Troponin Mutation Caused Diastolic Dysfunction and Experimental Treatment in Transgenic Mice with Cardiomyopathy

Xu¹,

Tian²,

Huang³

2014

JAMR

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“…Even a small amino acid deletion can lead to modifications in protein conformation that subsequently alter its function (Akhter et al, 2014). In healthy muscle, length-specific titin isoforms that vary in stiffness are routinely generated by selective amino acid deletion during posttranslational processing (Granzier and Labeit, 2004).…”

Section: Discussionmentioning

confidence: 99%

Decreased force enhancement in skeletal muscle sarcomeres with a deletion in titin

Powers

Nishikawa

Joumaa

et al. 2016

Journal of Experimental Biology

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In the cross-bridge theory, contractile force is produced by crossbridges that form between actin and myosin filaments. However, when a contracting muscle is stretched, its active force vastly exceeds the force that can be attributed to cross-bridges. This unexplained, enhanced force has been thought to originate in the giant protein titin, which becomes stiffer in actively compared with passively stretched sarcomeres by an unknown mechanism. We investigated this mechanism using a genetic mutation (mdm) with a small but crucial deletion in the titin protein. Myofibrils from normal and mdm mice were stretched from sarcomere lengths of 2.5 to 6.0 μm. Actively stretched myofibrils from normal mice were stiffer and generated more force than passively stretched myofibrils at all sarcomere lengths. No increase in stiffness and just a small increase in force were observed in actively compared with passively stretched mdm myofibrils. These results are in agreement with the idea that titin force enhancement stiffens and stabilizes the sarcomere during contraction and that this mechanism is lost with the mdm mutation.

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“…Recent studies demonstrated that the last 20 amino acids of the C-terminal end segment of TnI (residues 191–210 in cTnI) encoded by exon 8 with a highly conserved sequence is a Ca 2+ -modulated allosteric structure and interacts with tropomyosin (Zhang et al, 2011; Akhter et al, 2014). While the N-terminal extension of cTnI does not have definitive interaction with other known myofilament proteins, it plays a role in modulating the conformation of other regions of the cTnI molecule (Akhter et al, 2012).…”

Section: Structure-function Relationship Of Tni Isoformsmentioning

confidence: 99%

“…The C-terminal end segment (192–210) is the most conserved region of the TnI polypeptide chain (Jin et al, 2001) and a Ca 2+ -modulated allosteric structure in the troponin complex (Jin et al, 2001; Zhang et al, 2011; Wang et al, 2012a). R192H and R204H mutations in the C-terminal end segment of human cTnI cause restrictive cardiomyopathy (Mogensen et al, 2003; Gambarin et al, 2008) with alterations in the conformation and function of the TnI-TnT interface and increased binding affinity of cTnI for TnT (Akhter et al, 2014). …”

Section: Posttranslational Modificationsmentioning

confidence: 99%

TNNI1, TNNI2 and TNNI3: Evolution, regulation, and protein structure–function relationships

Sheng

Jin

2016

Gene

105

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Troponin I (TnI) is the inhibitory subunit of the troponin complex in the sarcomeric thin filament of striated muscle and plays a central role in the calcium regulation of contraction and relaxation. Vertebrate TnI has evolved into three isoforms encoded by three homologous genes: TNNI1 for slow skeletal muscle TnI, TNNI2 for fast skeletal muscle TnI and TNNI3 for cardiac TnI, which are expressed under muscle type-specific and developmental regulations. To summarize the current knowledge on the TnI isoform genes and products, this review focuses on the evolution, gene regulation, posttranslational modifications, and structure-function relationship of TnI isoform proteins. Their physiological and medical significances are also discussed.

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Restrictive cardiomyopathy mutations demonstrate functions of the C-terminal end-segment of troponin I

Cited by 15 publications

References 43 publications

Troponin Mutation Caused Diastolic Dysfunction and Experimental Treatment in Transgenic Mice with Cardiomyopathy

Troponin Mutation Caused Diastolic Dysfunction and Experimental Treatment in Transgenic Mice with Cardiomyopathy

Decreased force enhancement in skeletal muscle sarcomeres with a deletion in titin

TNNI1, TNNI2 and TNNI3: Evolution, regulation, and protein structure–function relationships

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