Comprehensive transcriptomic analysis shows disturbed calcium homeostasis and deregulation of T lymphocyte apoptosis in inclusion body myositis

Mridul Johari; Anna Vihola; Johanna Palmio; Manu Jokela; Per Harald Jonson; Jaakko Sarparanta; Sanna Huovinen; Marco Savarese; Peter Hackman; Bjarne Udd

doi:10.1007/s00415-022-11029-7

Comprehensive transcriptomic analysis shows disturbed calcium homeostasis and deregulation of T lymphocyte apoptosis in inclusion body myositis

Mridul Johari^*
, Anna Vihola
, Johanna Palmio
, Manu Jokela
, Per Harald Jonson
, Jaakko Sarparanta
, Sanna Huovinen
, Marco Savarese
, Peter Hackman
, Bjarne Udd

^*Tämän työn vastaava kirjoittaja

Patologian yksikkö

Tutkimustuotos: Artikkeli › Tieteellinen › vertaisarvioitu

17 Sitaatiot (Scopus)

23 Lataukset (Pure)

Abstrakti

Objective: Inclusion body myositis (IBM) has an unclear molecular etiology exhibiting both characteristic inflammatory T-cell activity and rimmed-vacuolar degeneration of muscle fibers. Using in-depth gene expression and splicing studies, we aimed at understanding the different components of the molecular pathomechanisms in IBM. Methods: We performed RNA-seq on RNA extracted from skeletal muscle biopsies of clinically and histopathologically defined IBM (n = 24), tibial muscular dystrophy (n = 6), and histopathologically normal group (n = 9). In a comprehensive transcriptomics analysis, we analyzed the differential gene expression, differential splicing and exon usage, downstream pathway analysis, and the interplay between coding and non-coding RNAs (micro RNAs and long non-coding RNAs). Results: We observe dysregulation of genes involved in calcium homeostasis, particularly affecting the T-cell activity and regulation, causing disturbed Ca²⁺-induced apoptotic pathways of T cells in IBM muscles. Additionally, LCK/p56, which is an essential gene in regulating the fate of T-cell apoptosis, shows increased expression and altered splicing usage in IBM muscles. Interpretation: Our analysis provides a novel understanding of the molecular mechanisms in IBM by showing a detailed dysregulation of genes involved in calcium homeostasis and its effect on T-cell functioning in IBM muscles. Loss of T-cell regulation is hypothesized to be involved in the consistent observation of no response to immune therapies in IBM patients. Our results show that loss of apoptotic control of cytotoxic T cells could indeed be one component of their abnormal cytolytic activity in IBM muscles.

Alkuperäiskieli	Englanti
Sivumäärä	13
Julkaisu	Journal of Neurology
Vuosikerta	269
Numero	8
DOI - pysyväislinkit	https://doi.org/10.1007/s00415-022-11029-7
Tila	Julkaistu - 2022
OKM-julkaisutyyppi	A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

Rahoitus

Open Access funding provided by the University of Helsinki including Helsinki University Central Hospital. This work was supported by the Folkhälsan Research Foundation, Doctoral program in Integrative Life Science (ILS) and Doctoral school in Health Sciences (DSHealth), University of Helsinki (MJ), the Päivikki and Sakari Sohlberg Foundation (MJ), the Biomedicum Helsinki Foundation (MJ), Finska läkaresällskapet (BU/MJ), the Finnish Medical Foundation (JP), the Paulo foundation (MS), the Jane and Aatos Erkko Foundation (PH) and the Sigrid Jusélius Foundation (BU). The authors would like to thank the patients and their families. We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant reference 203141/Z/16/Z) for the generation and initial processing of the sequencing data. We would like to thank CSC – IT Center for Science, Finland, for its computational resources. We thank Helena Luque, Merja Soininen, Talha Qureshi and Eini Penkkimäki for their technical assistance. We would like to thank Peter-Bram 't Hoen for his critical review of this manuscript.

Julkaisufoorumi-taso

Jufo-taso 1

!!ASJC Scopus subject areas

Neurology
Clinical Neurology

Pääsy asiakirjaan

10.1007/s00415-022-11029-7Lisenssi: CC BY

Johari2022_Article_ComprehensiveTranscriptomicAnaFinal published version, 3,27 MBLisenssi: CC BY

https://urn.fi/URN:NBN:fi:tuni-202203252755Lisenssi: CC BY

Siteeraa tätä

@article{682785048c1240e78afb87294749de74,

title = "Comprehensive transcriptomic analysis shows disturbed calcium homeostasis and deregulation of T lymphocyte apoptosis in inclusion body myositis",

abstract = "Objective: Inclusion body myositis (IBM) has an unclear molecular etiology exhibiting both characteristic inflammatory T-cell activity and rimmed-vacuolar degeneration of muscle fibers. Using in-depth gene expression and splicing studies, we aimed at understanding the different components of the molecular pathomechanisms in IBM. Methods: We performed RNA-seq on RNA extracted from skeletal muscle biopsies of clinically and histopathologically defined IBM (n = 24), tibial muscular dystrophy (n = 6), and histopathologically normal group (n = 9). In a comprehensive transcriptomics analysis, we analyzed the differential gene expression, differential splicing and exon usage, downstream pathway analysis, and the interplay between coding and non-coding RNAs (micro RNAs and long non-coding RNAs). Results: We observe dysregulation of genes involved in calcium homeostasis, particularly affecting the T-cell activity and regulation, causing disturbed Ca2+-induced apoptotic pathways of T cells in IBM muscles. Additionally, LCK/p56, which is an essential gene in regulating the fate of T-cell apoptosis, shows increased expression and altered splicing usage in IBM muscles. Interpretation: Our analysis provides a novel understanding of the molecular mechanisms in IBM by showing a detailed dysregulation of genes involved in calcium homeostasis and its effect on T-cell functioning in IBM muscles. Loss of T-cell regulation is hypothesized to be involved in the consistent observation of no response to immune therapies in IBM patients. Our results show that loss of apoptotic control of cytotoxic T cells could indeed be one component of their abnormal cytolytic activity in IBM muscles.",

keywords = "Calcium, Differential expression, Differential splicing, Inclusion body myositis, T cells",

author = "Mridul Johari and Anna Vihola and Johanna Palmio and Manu Jokela and Jonson, \{Per Harald\} and Jaakko Sarparanta and Sanna Huovinen and Marco Savarese and Peter Hackman and Bjarne Udd",

note = "Funding Information: Open Access funding provided by the University of Helsinki including Helsinki University Central Hospital. This work was supported by the Folkh{\"a}lsan Research Foundation, Doctoral program in Integrative Life Science (ILS) and Doctoral school in Health Sciences (DSHealth), University of Helsinki (MJ), the P{\"a}ivikki and Sakari Sohlberg Foundation (MJ), the Biomedicum Helsinki Foundation (MJ), Finska l{\"a}kares{\"a}llskapet (BU/MJ), the Finnish Medical Foundation (JP), the Paulo foundation (MS), the Jane and Aatos Erkko Foundation (PH) and the Sigrid Jus{\'e}lius Foundation (BU). Funding Information: The authors would like to thank the patients and their families. We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant reference 203141/Z/16/Z) for the generation and initial processing of the sequencing data. We would like to thank CSC – IT Center for Science, Finland, for its computational resources. We thank Helena Luque, Merja Soininen, Talha Qureshi and Eini Penkkim{\"a}ki for their technical assistance. We would like to thank Peter-Bram 't Hoen for his critical review of this manuscript. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

doi = "10.1007/s00415-022-11029-7",

language = "English",

volume = "269",

journal = "Journal of Neurology",

issn = "0340-5354",

publisher = "Springer",

number = "8",

}

TY - JOUR

T1 - Comprehensive transcriptomic analysis shows disturbed calcium homeostasis and deregulation of T lymphocyte apoptosis in inclusion body myositis

AU - Johari, Mridul

AU - Vihola, Anna

AU - Palmio, Johanna

AU - Jokela, Manu

AU - Jonson, Per Harald

AU - Sarparanta, Jaakko

AU - Huovinen, Sanna

AU - Savarese, Marco

AU - Hackman, Peter

AU - Udd, Bjarne

N1 - Funding Information: Open Access funding provided by the University of Helsinki including Helsinki University Central Hospital. This work was supported by the Folkhälsan Research Foundation, Doctoral program in Integrative Life Science (ILS) and Doctoral school in Health Sciences (DSHealth), University of Helsinki (MJ), the Päivikki and Sakari Sohlberg Foundation (MJ), the Biomedicum Helsinki Foundation (MJ), Finska läkaresällskapet (BU/MJ), the Finnish Medical Foundation (JP), the Paulo foundation (MS), the Jane and Aatos Erkko Foundation (PH) and the Sigrid Jusélius Foundation (BU). Funding Information: The authors would like to thank the patients and their families. We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant reference 203141/Z/16/Z) for the generation and initial processing of the sequencing data. We would like to thank CSC – IT Center for Science, Finland, for its computational resources. We thank Helena Luque, Merja Soininen, Talha Qureshi and Eini Penkkimäki for their technical assistance. We would like to thank Peter-Bram 't Hoen for his critical review of this manuscript. Publisher Copyright: © 2022, The Author(s).

PY - 2022

Y1 - 2022

N2 - Objective: Inclusion body myositis (IBM) has an unclear molecular etiology exhibiting both characteristic inflammatory T-cell activity and rimmed-vacuolar degeneration of muscle fibers. Using in-depth gene expression and splicing studies, we aimed at understanding the different components of the molecular pathomechanisms in IBM. Methods: We performed RNA-seq on RNA extracted from skeletal muscle biopsies of clinically and histopathologically defined IBM (n = 24), tibial muscular dystrophy (n = 6), and histopathologically normal group (n = 9). In a comprehensive transcriptomics analysis, we analyzed the differential gene expression, differential splicing and exon usage, downstream pathway analysis, and the interplay between coding and non-coding RNAs (micro RNAs and long non-coding RNAs). Results: We observe dysregulation of genes involved in calcium homeostasis, particularly affecting the T-cell activity and regulation, causing disturbed Ca2+-induced apoptotic pathways of T cells in IBM muscles. Additionally, LCK/p56, which is an essential gene in regulating the fate of T-cell apoptosis, shows increased expression and altered splicing usage in IBM muscles. Interpretation: Our analysis provides a novel understanding of the molecular mechanisms in IBM by showing a detailed dysregulation of genes involved in calcium homeostasis and its effect on T-cell functioning in IBM muscles. Loss of T-cell regulation is hypothesized to be involved in the consistent observation of no response to immune therapies in IBM patients. Our results show that loss of apoptotic control of cytotoxic T cells could indeed be one component of their abnormal cytolytic activity in IBM muscles.

AB - Objective: Inclusion body myositis (IBM) has an unclear molecular etiology exhibiting both characteristic inflammatory T-cell activity and rimmed-vacuolar degeneration of muscle fibers. Using in-depth gene expression and splicing studies, we aimed at understanding the different components of the molecular pathomechanisms in IBM. Methods: We performed RNA-seq on RNA extracted from skeletal muscle biopsies of clinically and histopathologically defined IBM (n = 24), tibial muscular dystrophy (n = 6), and histopathologically normal group (n = 9). In a comprehensive transcriptomics analysis, we analyzed the differential gene expression, differential splicing and exon usage, downstream pathway analysis, and the interplay between coding and non-coding RNAs (micro RNAs and long non-coding RNAs). Results: We observe dysregulation of genes involved in calcium homeostasis, particularly affecting the T-cell activity and regulation, causing disturbed Ca2+-induced apoptotic pathways of T cells in IBM muscles. Additionally, LCK/p56, which is an essential gene in regulating the fate of T-cell apoptosis, shows increased expression and altered splicing usage in IBM muscles. Interpretation: Our analysis provides a novel understanding of the molecular mechanisms in IBM by showing a detailed dysregulation of genes involved in calcium homeostasis and its effect on T-cell functioning in IBM muscles. Loss of T-cell regulation is hypothesized to be involved in the consistent observation of no response to immune therapies in IBM patients. Our results show that loss of apoptotic control of cytotoxic T cells could indeed be one component of their abnormal cytolytic activity in IBM muscles.

KW - Calcium

KW - Differential expression

KW - Differential splicing

KW - Inclusion body myositis

KW - T cells

U2 - 10.1007/s00415-022-11029-7

DO - 10.1007/s00415-022-11029-7

M3 - Article

AN - SCOPUS:85125499395

SN - 0340-5354

VL - 269

JO - Journal of Neurology

JF - Journal of Neurology

IS - 8

ER -

Comprehensive transcriptomic analysis shows disturbed calcium homeostasis and deregulation of T lymphocyte apoptosis in inclusion body myositis

Abstrakti

Rahoitus

Julkaisufoorumi-taso

!!ASJC Scopus subject areas

Pääsy asiakirjaan

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