Elevation of Cardiac Troponin T, But Not Cardiac Troponin I, in Patients With Neuromuscular Diseases

Rittoo, Dylmitr; Jones, Alan E.; Lecky, Bryan; Neithercut, Duncan

doi:10.1016/j.jacc.2014.03.027

Cited by 120 publications

(109 citation statements)

References 52 publications

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“…Interestingly, the up-regulation of troponins is a marker of heart failure (66). The differential expression of TnT relative to TnI in heart disease (67) supports the idea that differences in their expression are related to CM function. Further study is needed to understand how stiffness and shape regulate the expression of sarcomere proteins.…”

Section: Discussionmentioning

confidence: 83%

Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness

Ribeiro

Ang

et al. 2015

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

415

456

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Single cardiomyocytes contain myofibrils that harbor the sarcomerebased contractile machinery of the myocardium. Cardiomyocytes differentiated from human pluripotent stem cells (hPSC-CMs) have potential as an in vitro model of heart activity. However, their fetallike misalignment of myofibrils limits their usefulness for modeling contractile activity. We analyzed the effects of cell shape and substrate stiffness on the shortening and movement of labeled sarcomeres and the translation of sarcomere activity to mechanical output (contractility) in live engineered hPSC-CMs. Single hPSC-CMs were cultured on polyacrylamide substrates of physiological stiffness (10 kPa), and Matrigel micropatterns were used to generate physiological shapes (2,000-μm 2 rectangles with length:width aspect ratios of 5:1-7:1) and a mature alignment of myofibrils. Translation of sarcomere shortening to mechanical output was highest in 7:1 hPSC-CMs. Increased substrate stiffness and applied overstretch induced myofibril defects in 7:1 hPSC-CMs and decreased mechanical output. Inhibitors of nonmuscle myosin activity repressed the assembly of myofibrils, showing that subcellular tension drives the improved contractile activity in these engineered hPSC-CMs. Other factors associated with improved contractility were axially directed calcium flow, systematic mitochondrial distribution, more mature electrophysiology, and evidence of transverse-tubule formation. These findings support the potential of these engineered hPSC-CMs as powerful models for studying myocardial contractility at the cellular level.contractility | sarcomeres | cardiomyocyte | stem cell | single cell

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Section: Discussionmentioning

confidence: 83%

Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness

Ribeiro

Ang

et al. 2015

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

415

456

View full text Add to dashboard Cite

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“…Whereas injury to myocardium causes the simultaneous release of both cTnI and cTnT into the circulation, denervation and chronic injury of skeletal muscle may induce expression and release of cTnT, but not cTnI, from the skeletal muscle. Therefore, elevated circulating cTnT, but not cTnI, has been found in patients with various neuromuscular diseases and in healthy elderly patients without clinical cardiovascular disease 7, 9…”

Section: Introductionmentioning

confidence: 99%

Cardiac troponin T and fast skeletal muscle denervation in ageing

Feng

Dong

et al. 2017

J cachexia sarcopenia muscle

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BackgroundAgeing skeletal muscle undergoes chronic denervation, and the neuromuscular junction (NMJ), the key structure that connects motor neuron nerves with muscle cells, shows increased defects with ageing. Previous studies in various species have shown that with ageing, type II fast‐twitch skeletal muscle fibres show more atrophy and NMJ deterioration than type I slow‐twitch fibres. However, how this process is regulated is largely unknown. A better understanding of the mechanisms regulating skeletal muscle fibre‐type specific denervation at the NMJ could be critical to identifying novel treatments for sarcopenia. Cardiac troponin T (cTnT), the heart muscle‐specific isoform of TnT, is a key component of the mechanisms of muscle contraction. It is expressed in skeletal muscle during early development, after acute sciatic nerve denervation, in various neuromuscular diseases and possibly in ageing muscle. Yet the subcellular localization and function of cTnT in skeletal muscle is largely unknown.MethodsStudies were carried out on isolated skeletal muscles from mice, vervet monkeys, and humans. Immunoblotting, immunoprecipitation, and mass spectrometry were used to analyse protein expression, real‐time reverse transcription polymerase chain reaction was used to measure gene expression, immunofluorescence staining was performed for subcellular distribution assay of proteins, and electromyographic recording was used to analyse neurotransmission at the NMJ.ResultsLevels of cTnT expression in skeletal muscle increased with ageing in mice. In addition, cTnT was highly enriched at the NMJ region—but mainly in the fast‐twitch, not the slow‐twitch, muscle of old mice. We further found that the protein kinase A (PKA) RIα subunit was largely removed from, while PKA RIIα and RIIβ are enriched at, the NMJ—again, preferentially in fast‐twitch but not slow‐twitch muscle in old mice. Knocking down cTnT in fast skeletal muscle of old mice: (i) increased PKA RIα and reduced PKA RIIα at the NMJ; (ii) decreased the levels of gene expression of muscle denervation markers; and (iii) enhanced neurotransmission efficiency at NMJ.ConclusionsCardiac troponin T at the NMJ region contributes to NMJ functional decline with ageing mainly in the fast‐twitch skeletal muscle through interfering with PKA signalling. This knowledge could inform useful targets for prevention and therapy of age‐related decline in muscle function.

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“…[6][7][8] Recently, an elevation of plasma cTnT in the absence of cardiac troponin I (cTnI) in several neuromuscular diseases has been shown. 9 It has been suggested that diseased skeletal muscle tissue is an alternative source for elevated cTnT levels in certain neuromuscular conditions and dialysis patients.…”

mentioning

confidence: 99%

Elevated Plasma Cardiac Troponin T Levels Caused by Skeletal Muscle Damage in Pompe Disease

Wens

Schaaf

Michels

et al. 2016

Circ Cardiovasc Genet

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Background— Elevated plasma cardiac troponin T (cTnT) levels in patients with neuromuscular disorders may erroneously lead to the diagnosis of acute myocardial infarction or myocardial injury. Methods and Results— In 122 patients with Pompe disease, the relationship between cTnT, cardiac troponin I, creatine kinase (CK), CK-myocardial band levels, and skeletal muscle damage was assessed. ECG and echocardiography were used to evaluate possible cardiac disease. Patients were divided into classic infantile, childhood-onset, and adult-onset patients. cTnT levels were elevated in 82% of patients (median 27 ng/L, normal values <14 ng/L). Cardiac troponin I levels were normal in all patients, whereas CK-myocardial band levels were increased in 59% of patients. cTnT levels correlated with CK levels in all 3 subgroups ( P <0.001). None of the abnormal ECGs recorded in 21 patients were indicative of acute myocardial infarction, and there were no differences in cTnT levels between patients with and without (n=90) abnormalities on ECG (median 28 ng/L in both groups). The median left ventricular mass index measured with echocardiography was normal in all the 3 subgroups. cTnT mRNA expression in skeletal muscle was not detectable in controls but was strongly induced in patients with Pompe disease. cTnT protein was identified by mass spectrometry in patient-derived skeletal muscle tissue. Conclusions— Elevated plasma cTnT levels in patients with Pompe disease are associated with skeletal muscle damage, rather than acute myocardial injury. Increased cTnT levels in Pompe disease and likely other neuromuscular disorders should be interpreted with caution to avoid unnecessary cardiac interventions.

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Elevation of Cardiac Troponin T, But Not Cardiac Troponin I, in Patients With Neuromuscular Diseases

Cited by 120 publications

References 52 publications

Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness

Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness

Cardiac troponin T and fast skeletal muscle denervation in ageing

Elevated Plasma Cardiac Troponin T Levels Caused by Skeletal Muscle Damage in Pompe Disease

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