Delineation of molecular pathways involved in cardiomyopathies caused by Troponin T Mutations

Jennifer E. Gilda, Xianyin Lai, Frank Witzmann, Aldrin V. Gomes

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Familial hypertrophic cardiomyopathy (FHC) is associated with mild to severe cardiac problems and is the leading cause of sudden death in young people and athletes. Although the genetic basis for FHC is well-established, the molecular mechanisms that ultimately lead to cardiac dysfunction are not well understood. To obtain important insights into the molecular mechanism(s) involved in FHC, hearts from two FHC troponin T models (Ile79Asn [I79N] and Arg278Cys [R278C]) were investigated using label-free proteomics and metabolomics. Mutations in troponin T are the third most common cause of FHC, and the I79N mutation is associated with a high risk of sudden cardiac death. Most FHC-causing mutations, including I79N, increase the Ca2+ sensitivity of the myofilament; however, the R278C mutation does not alter Ca2+ sensitivity and is associated with a better prognosis than most FHC mutations. Out of more than 1200 identified proteins, 53 and 76 proteins were differentially expressed in I79N and R278C hearts, respectively, when compared with wild-type hearts. Interestingly, more than 400 proteins were differentially expressed when the I79N and R278C hearts were directly compared. The three major pathways affected in I79N hearts relative to R278C and wild-type hearts were the ubiquitin-proteasome system, antioxidant systems, and energy production pathways. Further investigation of the proteasome system using Western blotting and activity assays showed that proteasome dysfunction occurs in I79N hearts. Metabolomic results corroborate the proteomic data and suggest the glycolytic, citric acid, and electron transport chain pathways are important pathways that are altered in I79N hearts relative to R278C or wild-type hearts. Our findings suggest that impaired energy production and protein degradation dysfunction are important mechanisms in FHCs associated with poor prognosis and that cardiac hypertrophy is not likely needed for a switch from fatty acid to glucose metabolism.

Original languageEnglish (US)
Pages (from-to)1962-1981
Number of pages20
JournalMolecular and Cellular Proteomics
Volume15
Issue number6
DOIs
StatePublished - Jun 1 2016

Fingerprint

Troponin T
Familial Hypertrophic Cardiomyopathy
Cardiomyopathies
Mutation
Proteasome Endopeptidase Complex
Metabolomics
Proteomics
Proteins
Myofibrils
Sudden Cardiac Death
Cardiomegaly
Electron Transport
Ubiquitin
Sudden Death
Metabolism
Citric Acid
Athletes
Proteolysis
Labels
Cause of Death

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Analytical Chemistry

Cite this

Delineation of molecular pathways involved in cardiomyopathies caused by Troponin T Mutations. / Gilda, Jennifer E.; Lai, Xianyin; Witzmann, Frank; Gomes, Aldrin V.

In: Molecular and Cellular Proteomics, Vol. 15, No. 6, 01.06.2016, p. 1962-1981.

Research output: Contribution to journalArticle

Gilda, Jennifer E. ; Lai, Xianyin ; Witzmann, Frank ; Gomes, Aldrin V. / Delineation of molecular pathways involved in cardiomyopathies caused by Troponin T Mutations. In: Molecular and Cellular Proteomics. 2016 ; Vol. 15, No. 6. pp. 1962-1981.
@article{5761895e1e9b40ed93ace16fda6bc840,
title = "Delineation of molecular pathways involved in cardiomyopathies caused by Troponin T Mutations",
abstract = "Familial hypertrophic cardiomyopathy (FHC) is associated with mild to severe cardiac problems and is the leading cause of sudden death in young people and athletes. Although the genetic basis for FHC is well-established, the molecular mechanisms that ultimately lead to cardiac dysfunction are not well understood. To obtain important insights into the molecular mechanism(s) involved in FHC, hearts from two FHC troponin T models (Ile79Asn [I79N] and Arg278Cys [R278C]) were investigated using label-free proteomics and metabolomics. Mutations in troponin T are the third most common cause of FHC, and the I79N mutation is associated with a high risk of sudden cardiac death. Most FHC-causing mutations, including I79N, increase the Ca2+ sensitivity of the myofilament; however, the R278C mutation does not alter Ca2+ sensitivity and is associated with a better prognosis than most FHC mutations. Out of more than 1200 identified proteins, 53 and 76 proteins were differentially expressed in I79N and R278C hearts, respectively, when compared with wild-type hearts. Interestingly, more than 400 proteins were differentially expressed when the I79N and R278C hearts were directly compared. The three major pathways affected in I79N hearts relative to R278C and wild-type hearts were the ubiquitin-proteasome system, antioxidant systems, and energy production pathways. Further investigation of the proteasome system using Western blotting and activity assays showed that proteasome dysfunction occurs in I79N hearts. Metabolomic results corroborate the proteomic data and suggest the glycolytic, citric acid, and electron transport chain pathways are important pathways that are altered in I79N hearts relative to R278C or wild-type hearts. Our findings suggest that impaired energy production and protein degradation dysfunction are important mechanisms in FHCs associated with poor prognosis and that cardiac hypertrophy is not likely needed for a switch from fatty acid to glucose metabolism.",
author = "Gilda, {Jennifer E.} and Xianyin Lai and Frank Witzmann and Gomes, {Aldrin V.}",
year = "2016",
month = "6",
day = "1",
doi = "10.1074/mcp.M115.057380",
language = "English (US)",
volume = "15",
pages = "1962--1981",
journal = "Molecular and Cellular Proteomics",
issn = "1535-9476",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "6",

}

TY - JOUR

T1 - Delineation of molecular pathways involved in cardiomyopathies caused by Troponin T Mutations

AU - Gilda, Jennifer E.

AU - Lai, Xianyin

AU - Witzmann, Frank

AU - Gomes, Aldrin V.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - Familial hypertrophic cardiomyopathy (FHC) is associated with mild to severe cardiac problems and is the leading cause of sudden death in young people and athletes. Although the genetic basis for FHC is well-established, the molecular mechanisms that ultimately lead to cardiac dysfunction are not well understood. To obtain important insights into the molecular mechanism(s) involved in FHC, hearts from two FHC troponin T models (Ile79Asn [I79N] and Arg278Cys [R278C]) were investigated using label-free proteomics and metabolomics. Mutations in troponin T are the third most common cause of FHC, and the I79N mutation is associated with a high risk of sudden cardiac death. Most FHC-causing mutations, including I79N, increase the Ca2+ sensitivity of the myofilament; however, the R278C mutation does not alter Ca2+ sensitivity and is associated with a better prognosis than most FHC mutations. Out of more than 1200 identified proteins, 53 and 76 proteins were differentially expressed in I79N and R278C hearts, respectively, when compared with wild-type hearts. Interestingly, more than 400 proteins were differentially expressed when the I79N and R278C hearts were directly compared. The three major pathways affected in I79N hearts relative to R278C and wild-type hearts were the ubiquitin-proteasome system, antioxidant systems, and energy production pathways. Further investigation of the proteasome system using Western blotting and activity assays showed that proteasome dysfunction occurs in I79N hearts. Metabolomic results corroborate the proteomic data and suggest the glycolytic, citric acid, and electron transport chain pathways are important pathways that are altered in I79N hearts relative to R278C or wild-type hearts. Our findings suggest that impaired energy production and protein degradation dysfunction are important mechanisms in FHCs associated with poor prognosis and that cardiac hypertrophy is not likely needed for a switch from fatty acid to glucose metabolism.

AB - Familial hypertrophic cardiomyopathy (FHC) is associated with mild to severe cardiac problems and is the leading cause of sudden death in young people and athletes. Although the genetic basis for FHC is well-established, the molecular mechanisms that ultimately lead to cardiac dysfunction are not well understood. To obtain important insights into the molecular mechanism(s) involved in FHC, hearts from two FHC troponin T models (Ile79Asn [I79N] and Arg278Cys [R278C]) were investigated using label-free proteomics and metabolomics. Mutations in troponin T are the third most common cause of FHC, and the I79N mutation is associated with a high risk of sudden cardiac death. Most FHC-causing mutations, including I79N, increase the Ca2+ sensitivity of the myofilament; however, the R278C mutation does not alter Ca2+ sensitivity and is associated with a better prognosis than most FHC mutations. Out of more than 1200 identified proteins, 53 and 76 proteins were differentially expressed in I79N and R278C hearts, respectively, when compared with wild-type hearts. Interestingly, more than 400 proteins were differentially expressed when the I79N and R278C hearts were directly compared. The three major pathways affected in I79N hearts relative to R278C and wild-type hearts were the ubiquitin-proteasome system, antioxidant systems, and energy production pathways. Further investigation of the proteasome system using Western blotting and activity assays showed that proteasome dysfunction occurs in I79N hearts. Metabolomic results corroborate the proteomic data and suggest the glycolytic, citric acid, and electron transport chain pathways are important pathways that are altered in I79N hearts relative to R278C or wild-type hearts. Our findings suggest that impaired energy production and protein degradation dysfunction are important mechanisms in FHCs associated with poor prognosis and that cardiac hypertrophy is not likely needed for a switch from fatty acid to glucose metabolism.

UR - http://www.scopus.com/inward/record.url?scp=84973392014&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84973392014&partnerID=8YFLogxK

U2 - 10.1074/mcp.M115.057380

DO - 10.1074/mcp.M115.057380

M3 - Article

C2 - 27022107

AN - SCOPUS:84973392014

VL - 15

SP - 1962

EP - 1981

JO - Molecular and Cellular Proteomics

JF - Molecular and Cellular Proteomics

SN - 1535-9476

IS - 6

ER -