Increasing mammalian cardiomyocyte contractility with residues identified in trout troponin C

Gillis, Todd E.; Liang, Bo; Chung, Franca; Tibbits, Glen F.

doi:10.1152/physiolgenomics.00007.2005

Cited by 30 publications

(39 citation statements)

References 36 publications

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“…The end result is an increased mobility of tropomyosin (Tm) over the surface of the actin filaments, allowing for the formation of force-generating cross-bridges between actin and myosin (13,19). Manipulation of the Ca 2ϩ sensitivity of the contractile element can affect the amount of force generated as well as the rate at which it is generated (17,19). Such changes in contractile function can be caused by alterations to the proteins that compose the contractile element (17,22,67).…”

Section: Diaphragmatic Myofilament Function Becomes Increasingly Impamentioning

confidence: 99%

“…Manipulation of the Ca 2ϩ sensitivity of the contractile element can affect the amount of force generated as well as the rate at which it is generated (17,19). Such changes in contractile function can be caused by alterations to the proteins that compose the contractile element (17,22,67). The loss of diaphragm function during the development of HF may therefore be due, in part, to changes to the contractile elements of the muscle fibers composing the diaphragm.…”

Section: Diaphragmatic Myofilament Function Becomes Increasingly Impamentioning

confidence: 99%

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Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice

Gillis

Klaiman

Foster

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Gillis TE, Klaiman JM, Foster A, Platt MJ, Huber JS, Corso MY, Simpson JA. Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice. Am J Physiol Heart Circ Physiol 310: H572-H586, 2016. First published December 23, 2015 doi:10.1152/ajpheart.00773.2015.-Dyspnea and reduced exercise capacity, caused, in part, by respiratory muscle dysfunction, are common symptoms in patients with heart failure (HF). However, the etiology of diaphragmatic dysfunction has not been identified. To investigate the effects of HF on diaphragmatic function, models of HF were surgically induced in CD-1 mice by transverse aortic constriction (TAC) and acute myocardial infarction (AMI), respectively. Assessment of myocardial function, isolated diaphragmatic strip function, myofilament force-pCa relationship, and phosphorylation status of myofilament proteins was performed at either 2 or 18 wk postsurgery. Echocardiography and invasive hemodynamics revealed development of HF by 18 wk postsurgery in both models. In vitro diaphragmatic force production was preserved in all groups while morphometric analysis revealed diaphragmatic atrophy and fibrosis in 18 wk TAC and AMI groups. Isometric force-pCa measurements of myofilament preparations revealed reduced Ca 2ϩ sensitivity of force generation and force generation at half-maximum and maximum Ca 2ϩ activation in 18 wk TAC. The rate of force redevelopment (k tr) was reduced in all HF groups at high levels of Ca 2ϩ activation. Finally, there were significant changes in the myofilament phosphorylation status of the 18 wk TAC group. This includes a decrease in the phosphorylation of troponin T, desmin, myosin light chain (MLC) 1, and MLC 2 as well as a shift in myosin isoforms. These results indicate that there are multiple changes in diaphragmatic myofilament function, which are specific to the type and stage of HF and occur before overt impairment of in vitro force production.calcium-activated force generation; diaphragm function; heart failure; myofilament proteins; protein phosphorylation HEART FAILURE (HF) is a global health problem and is one of the most prevalent causes of morbidity in all ages (15,46). Patients with HF are frequently limited in their daily activities by dyspnea and exertional fatigue. One potential cause is inspiratory muscle (primarily the diaphragm) dysfunction. De Troyer and colleagues (11) first noted compromised inspiratory muscle function in patients with cardiac dysfunction. Respiratory muscle dysfunction is now considered a salient feature of patients (11,21,23,35,36,62) and animals (7-9, 24, 28, 53, 58) with HF. Currently, little is known about the development of respiratory muscle dysfunction during the early onset of HF.In patients with HF, eupneic pressure generation is increased (28, 58), which is considered to impose a stress on the diaphragm. This chronic workload on the diaphragm is thought to overwork the muscle leading to development of a myopathy characterized by a shift in fiber type, atrophy, and co...

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Section: Diaphragmatic Myofilament Function Becomes Increasingly Impamentioning

confidence: 99%

Section: Diaphragmatic Myofilament Function Becomes Increasingly Impamentioning

confidence: 99%

Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice

Gillis

Klaiman

Foster

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…Salmonid cTnC has a greater than two-fold Ca 2+ affinity over mammalian cTnC (Gillis et al, 2003) with four sequence differences between the mammalian and salmonid homologues responsible for the high Ca 2+ affinity: D2N, V28I, L29Q, and G30D (NIQD). When the mammalian residues were mutated to the salmonidequivalent, including L29 to Q29, the Ca 2+ -binding affinities of the mammalian cTnC mutants increased to the level of the salmonid cTnC (Gillis et al, 2005). Seven years after the initial FHC cTnC report, a large study cohort of 1025 unrelated patients was screened for FHC mutations and four novel cTnC mutations were reported: A8V, C84Y, E134D and D145E (Landstrom et al, 2008).…”

Section: In Vitro Analyses and Human Cardiac Tnc Mutation Studiesmentioning

confidence: 99%

Familial Hypertrophic Cardiomyopathy-Related Troponin Mutations and Sudden Cardiac Death

Dewar¹,

Liang²,

Li³

et al. 2012

Cardiomyopathies - From Basic Research to Clinical Management

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“…The comparatively high Ca 2+ sensitivity of the trout heart is due in part to trout cTnC having 2.3-fold the Ca 2+ affinity of human cTnC (Gillis et al, 2000). The residues in trout cTnC responsible for its comparatively high Ca 2+ affinity are Asn2, Ile28, Gln29 and Asp30 (Gillis et al, 2005). When human cTnC was mutated to contain these residues and the mutant protein was incorporated into rabbit cardiac myocytes, the Ca 2+ sensitivity of force generation was increased 2-fold (Gillis et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…The residues in trout cTnC responsible for its comparatively high Ca 2+ affinity are Asn2, Ile28, Gln29 and Asp30 (Gillis et al, 2005). When human cTnC was mutated to contain these residues and the mutant protein was incorporated into rabbit cardiac myocytes, the Ca 2+ sensitivity of force generation was increased 2-fold (Gillis et al, 2005). This clearly shows that trout cTnC can increase the Ca 2+ sensitivity of force generation but indicates that other mechanisms are involved in the comparatively high Ca 2+ sensitivity of the trout heart.…”

Section: Introductionmentioning

confidence: 99%

The influence of trout cardiac troponin I and PKA phosphorylation on the Ca2+ affinity of the cardiac troponin complex

Kirkpatrick

Robertson

Klaiman

et al. 2011

Journal of Experimental Biology

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SUMMARYThe trout heart is 10-fold more sensitive to Ca 2+ than the mammalian heart. This difference is due, in part, to cardiac troponin C (cTnC) from trout having a greater Ca 2+ affinity than human cTnC. To determine what other proteins are involved, we cloned cardiac troponin I (cTnI) from the trout heart and determined how it alters the Ca 2+ affinity of a cTn complex containing all mammalian components (mammalian cTn). Ca 2+ activation of the complex was characterized using a human cTnC mutant that contains anilinonapthalenesulfote iodoacetamide attached to Cys53. When the cTn complex containing labeled human cTnC was titrated with Ca 2+, its fluorescence changed, reaching an asymptote upon saturation. Our results reveal that trout cTnI lacks the N-terminal extension found in cTnI from all other vertebrate groups. This protein domain contains two targets (Ser23 and Ser24) for protein kinase A (PKA) and protein kinase C. When these are phosphorylated, the rate of cardiomyocyte relaxation increases. When rat cTnI in the mammalian cTn complex was replaced with trout cTnI, the Ca 2+ affinity was increased ~1.8-fold. This suggests that trout cTnI contributes to the high Ca 2+ sensitivity of the trout heart. Treatment of the two cTn complexes with PKA decreased the Ca 2+ affinity of both complexes. However, the change for the complex containing rat cTnI was 2.2-fold that of the complex containing trout cTnI. This suggests that the phosphorylation of trout cTnI does not play as significant a role in regulating cTn function in trout.

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Increasing mammalian cardiomyocyte contractility with residues identified in trout troponin C

Cited by 30 publications

References 36 publications

Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice

Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice

Familial Hypertrophic Cardiomyopathy-Related Troponin Mutations and Sudden Cardiac Death

The influence of trout cardiac troponin I and PKA phosphorylation on the Ca2+ affinity of the cardiac troponin complex

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