Titin M-line insertion sequence 7 is required for proper cardiac function in mice.
Alternative splicing
Cardiomyopathy
Heart failure
Mex5
Titin
is7
Journal
Journal of cell science
ISSN: 1477-9137
Titre abrégé: J Cell Sci
Pays: England
ID NLM: 0052457
Informations de publication
Date de publication:
15 09 2021
15 09 2021
Historique:
received:
25
03
2021
accepted:
06
08
2021
pubmed:
18
8
2021
medline:
27
10
2021
entrez:
17
8
2021
Statut:
ppublish
Résumé
Titin is a giant sarcomeric protein that is involved in a large number of functions, with a primary role in skeletal and cardiac sarcomere organization and stiffness. The titin gene (TTN) is subject to various alternative splicing events, but in the region that is present at the M-line, the only exon that can be spliced out is Mex5, which encodes for the insertion sequence 7 (is7). Interestingly, in the heart, the majority of titin isoforms are Mex5+, suggesting a cardiac role for is7. Here, we performed comprehensive functional, histological, transcriptomic, microscopic and molecular analyses of a mouse model lacking the Ttn Mex5 exon (ΔMex5), and revealed that the absence of the is7 is causative for dilated cardiomyopathy. ΔMex5 mice showed altered cardiac function accompanied by increased fibrosis and ultrastructural alterations. Abnormal expression of excitation-contraction coupling proteins was also observed. The results reported here confirm the importance of the C-terminal region of titin in cardiac function and are the first to suggest a possible relationship between the is7 and excitation-contraction coupling. Finally, these findings give important insights for the identification of new targets in the treatment of titinopathies.
Identifiants
pubmed: 34401916
pii: 271843
doi: 10.1242/jcs.258684
pmc: PMC8466004
pii:
doi:
Substances chimiques
Connectin
0
DNA Transposable Elements
0
Protein Kinases
EC 2.7.-
titin protein, mouse
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : R35 HL144998
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35HL144998
Pays : United States
Organisme : Marie Curie
ID : Staff exchange project: Muscle Stress Relief (645648)
Pays : United Kingdom
Informations de copyright
© 2021. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing or financial interests.
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