CARDIAC TROPONIN T MEDIATED AUTOIMMUNE RESPONSE AND ITS ROLE IN SKELETAL MUSCLE AGING

Abstract Cardiac troponin T (cTnT), a key component of contractile machinery essential for muscle contraction, is also expressed in skeletal muscle under certain conditions (e.g. neuromuscular diseases and aging). We have reported that skeletal muscle cTnT regulates neuromuscular junction denervation preferentially in fast skeletal muscle of old mice. Here, we further report that cTnT is also enriched within some myofibers, and/or along microvascular walls in old mice fast skeletal muscle. Strikingly, immunoglobulin G (IgG), together with markers of complement system activation, cell death (necroptosis or apoptosis), and macrophage infiltration, were all found to be co-localized with cTnT and IgG in those areas. In addition, elevated cTnT and IgG are associated with lower dystrophin expression on muscle fiber membrane, lower muscle capillary density, and reduced muscle performance (wire hanging test). Using purified recombinant TnT proteins, we confirmed that only cTnT, but not slow or fast skeletal muscle TnT1 or TnT3, was detected by immunoblot using sera from old (but not young) mice with pre-determined elevated cTnT and IgG in their skeletal muscle, indicating the existence of anti-cTnT autoantibodies in sera (previously found in human blood) and skeletal muscle of old mice. Immunoblotting further revealed that the age related changes in skeletaI muscle cTnT and IgG are more prominent in fast skeletal muscle than in slow. Importantly, elevated cTnT and IgG were also detected in skeletal muscles from 4 older adults (65-70 yrs, IMFIT). Our finding suggests a novel autoimmune mechanism mediated by cTnT that underlies age related skeletal muscle abnormalities and dysfunction.

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CARDIAC TROPONIN T AND FAST SKELETAL MUSCLE DENERVATION IN OLDER ADULTS

The Gerontologist ◽

10.1093/geront/gnw162.1418 ◽

2016 ◽

Vol 56 (Suppl_3) ◽

pp. 350-350

Keyword(s):

Older Adults ◽

Skeletal Muscle ◽

Cardiac Troponin ◽

Troponin T ◽

Cardiac Troponin T ◽

Muscle Denervation ◽

Fast Skeletal Muscle

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Cardiac troponin T and fast skeletal muscle denervation in ageing

Journal of Cachexia Sarcopenia and Muscle ◽

10.1002/jcsm.12204 ◽

2017 ◽

Vol 8 (5) ◽

pp. 808-823 ◽

Cited By ~ 10

Author(s):

Zherong Xu ◽

Xin Feng ◽

Juan Dong ◽

Zhong-Min Wang ◽

Jingyun Lee ◽

...

Keyword(s):

Skeletal Muscle ◽

Cardiac Troponin ◽

Troponin T ◽

Cardiac Troponin T ◽

Muscle Denervation ◽

Fast Skeletal Muscle

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Cardiac troponin I, cardiac troponin T, and creatine kinase MB in dialysis patients without ischemic heart disease: evidence of cardiac troponin T expression in skeletal muscle

Clinical Chemistry ◽

10.1093/clinchem/43.6.976 ◽

1997 ◽

Vol 43 (6) ◽

pp. 976-982 ◽

Cited By ~ 133

Author(s):

Mary D McLaurin ◽

Fred S Apple ◽

Ellen M Voss ◽

Charles A Herzog ◽

Scott W Sharkey

Keyword(s):

Skeletal Muscle ◽

Heart Disease ◽

Ischemic Heart Disease ◽

Cardiac Troponin ◽

First Generation ◽

Troponin T ◽

Ischemic Heart ◽

Cardiac Troponin T ◽

Dialysis Patients ◽

Acute Ischemic Heart Disease

Abstract Serum cardiac troponin T (cTnT) concentrations are frequently increased in chronic dialysis patients as measured by the first-generation ELISA immunoassay, as is creatine kinase (CK) MB mass in the absence of acute ischemic heart disease. We designed this study to compare four serum markers of myocardial injury [CK-MB mass, first-generation ELISA cTnT, second-generation Enzymun cTnT, and cardiac troponin I (cTnI)] in dialysis patients without acute ischemic heart disease. We also evaluated skeletal muscle from dialysis patients as a potential source of serum cTnT. No patients in the clinical evaluation group (n = 24) studied by history and by physical examination, electrocardiography, and two-dimensional echocardiography had evidence of ischemic heart disease. Biochemical markers were measured in serial predialysis blood samples with specific monoclonal antibody-based immunoassays. For several patients at least one sample measured above the upper reference limit: CK-MB, 7 of 24 (30%); ELISA cTnT, 17 of 24 (71%); Enzymun cTnT, 3 of 18 (17%); and cTnI, 1 of 24 (4%). In a separate group of dialysis patients (n = 5), expression of cTnT, but not cTnI, was demonstrated by Western blot analysis in 4 of 5 skeletal muscle biopsies. Chronic dialysis patients without acute ischemic heart disease frequently had increased serum CK-MB and cTnT. The specificity of the second-generation cTnT (Enzymun) assay was improved over that of the first-generation (ELISA) assay; cTnI was the most specific of the currently available biochemical markers. cTnT, but not cTnI, was expressed in the skeletal muscle of dialysis patients.

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Multicenter evaluation of a second-generation assay for cardiac troponin T

Clinical Chemistry ◽

10.1093/clinchem/43.10.1877 ◽

1997 ◽

Vol 43 (10) ◽

pp. 1877-1884 ◽

Cited By ~ 62

Author(s):

Hannsjörg Baum ◽

Siegmund Braun ◽

Willie Gerhardt ◽

Georges Gilson ◽

Gerd Hafner ◽

...

Keyword(s):

Skeletal Muscle ◽

Cardiac Troponin ◽

First Generation ◽

Second Generation ◽

Troponin T ◽

Myocardial Damage ◽

Cross Reactivity ◽

Cardiac Troponin T ◽

Marathon Runners ◽

Assay Time

Abstract We report on the evaluation of the second-generation assay for cardiac troponin T (cTnT) on the Enzymun®system. This new assay is completely specific for the cardiac isoform of TnT, utilizing two cardiospecific monoclonal antibodies. The assay time is reduced to 45 min. The interassay precision shows a median CV of 5.5%; 20% interassay CV was found between 0.05 and 0.1 μg/L. The cardiosensitivity of the second-generation cTnT assay in patients with ischemic myocardial injury appears equivalent when compared with the first-generation assay. We found no falsely positive results in patients with skeletal muscle damage including multitraumas, surgery patients, and marathon runners who showed highly increased values with the unspecific first-generation assay. In Duchenne disease cTnT was still increased, but to a much lower extent. cTnT remains increased in renal failure, but to a lesser degree than with the first-generation assay. The cause of this increase remains unclear. Although a cross-reactivity of skeletal muscle TnT in the second-generation assay could be excluded by our findings, minor myocardial damage or expression of the cardiac isoform of TnT in regenerating muscles cannot be ruled out in those cases with apparently falsely increased cTnT values. The second-generation cTnT assay is a step forward in the combination of cardiosensitivity and cardiospecificity in biochemical markers for diagnosis of heart disease.

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Effects of exercise on plasma myosin heavy chain fragments and MRI of skeletal muscle

Journal of Applied Physiology ◽

10.1152/jappl.1992.72.2.656 ◽

1992 ◽

Vol 72 (2) ◽

pp. 656-663 ◽

Cited By ~ 69

Author(s):

J. Mair ◽

A. Koller ◽

E. Artner-Dworzak ◽

C. Haid ◽

K. Wicke ◽

...

Keyword(s):

Skeletal Muscle ◽

Cardiac Troponin ◽

Troponin T ◽

Plasma Concentrations ◽

Eccentric Contractions ◽

Cardiac Troponin T ◽

Skeletal Muscle Myosin ◽

Slow Skeletal Muscle ◽

Slow Twitch ◽

Muscle Myosin

The effects of a single series of high-force eccentric contractions involving the quadriceps muscle group (single leg) on plasma concentrations of muscle proteins were examined as a function of time, in the context of measurements of torque production and magnetic resonance imaging (MRI) of the involved muscle groups. Plasma concentrations of slow-twitch skeletal (cardiac beta-type) myosin heavy chain (MHC) fragments, myoglobin, creatine kinase (CK), and cardiac troponin T were measured in blood samples of six healthy male volunteers before and 2 h after 70 eccentric contractions of the quadriceps femoris muscle. Screenings were conducted 1, 2, 3, 6, 9, and 13 days later. To visualize muscle injury, MRI of the loaded and unloaded thighs was performed 3, 6, and 9 days after the eccentric exercise bout. Force generation of the knee extensors was monitored on a dynamometer (Cybex II+) parallel to blood sampling. Exercise resulted in a biphasic myoglobin release profile, delayed CK and MHC peaks. Increased MHC fragment concentrations of slow skeletal muscle myosin occurred in late samples of all participants, which indicated a degradation of slow skeletal muscle myosin. Because cardiac troponin T was within the normal range in all samples, which excluded a protein release from the heart (cardiac beta-type MHC), this finding provides evidence for an injury of slow-twitch skeletal muscle fibers in response to eccentric contractions. Muscle action revealed delayed reversible increases in MRI signal intensities on T2-weighted images of the loaded vastus intermedius and deep parts of the vastus lateralis. We attributed MRI signal changes due to edema in part to slow skeletal muscle fiber injury.(ABSTRACT TRUNCATED AT 250 WORDS)

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