Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 44, Issue 6, Pages 983-991Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2008.02.272
Keywords
titin; alternative splicing; isoforms; passive tension; heart
Categories
Funding
- NHLBI NIH HHS [R37 HL82900, R01 HL077196, R01 HL077196-03, R37 HL082900, R37 HL082900-03, R01 HL77196, R37 HL082900-02] Funding Source: Medline
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Titin is a very large alternatively spliced protein that performs multiple functions in heart and skeletal muscles. A rat strain is described with an autosomal dominant mutation that alters the isoform expression of titin. While wild type animals go through a developmental program where the 3.0 MDa N2B becomes the major isoform expressed by two to three weeks after birth (-85%), the appearance of the N2B is markedly delayed in heterozygotes and never reaches more than 50% of the titin in the adult. Homozygote mutants express a giant titin of the N2BA isoform type (3.9 MDa) that persists as the primary titin species through ages of more than one and a half years. The mutation does not affect the isoform switching of troponin T, a protein that is also alternatively spliced with developmental changes. The basis for the apparently greater size of the giant titin in homozygous mutants was not determined, but the additional length was not due to inclusion of sequence from larger numbers of PEVK exons or the Novex III exon. Passive tension measurements using isolated cardiomyocytes from homozygous mutants showed that cells could be stretched to sarcomere lengths greater than 4 mu m without breakage. This novel rat model should be useful for exploring the potential role of titin in the Frank-Starling relationship and mechano-sensing/signaling mechanisms. (c) 2008 Elsevier Inc. All rights reserved.
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