Greaser Marion L, Warren Chad M, Esbona Karla, Guo Wei, Duan Yingli, Parrish Amanda M, Krzesinski Paul R, Norman Holly S, Dunning Sandra, Fitzsimons Daniel P, Moss Richard L
Muscle Biology Laboratory, University of Wisconsin-Madison, 1805 Linden Drive, Madison, WI 53706, USA.
Muscle Biology Laboratory, University of Wisconsin-Madison, 1805 Linden Drive, Madison, WI 53706, USA.
J Mol Cell Cardiol. 2008 Jun;44(6):983-991. doi: 10.1016/j.yjmcc.2008.02.272. Epub 2008 Feb 23.
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 (approximately 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 mum 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.
肌联蛋白是一种非常大的可变剪接蛋白,在心肌和骨骼肌中发挥多种功能。本文描述了一种大鼠品系,其常染色体显性突变改变了肌联蛋白的异构体表达。野生型动物在发育过程中,出生后两到三周时3.0 MDa的N2B异构体成为主要表达的异构体(约85%),而杂合子中N2B的出现明显延迟,在成年动物中其含量从未超过肌联蛋白的50%。纯合子突变体表达N2BA异构体类型的巨大肌联蛋白(3.9 MDa),这种异构体在一岁半以上的动物中一直作为主要的肌联蛋白种类存在。该突变不影响肌钙蛋白T的异构体转换,肌钙蛋白T也是一种随着发育变化而可变剪接的蛋白。纯合子突变体中巨大肌联蛋白明显更大的原因尚未确定,但额外的长度并非源于包含了更多数量的PEVK外显子或Novex III外显子的序列。使用纯合子突变体的分离心肌细胞进行的被动张力测量表明,细胞可以被拉伸至肌节长度大于4μm而不破裂。这种新型大鼠模型对于探索肌联蛋白在Frank-Starling关系以及机械传感/信号传导机制中的潜在作用应该是有用的。