Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling.

Muscular dystrophy with myositis (mdm) is a recessive mouse mutation that is caused by a small deletion in the giant elastic muscle protein titin. Homozygous mdm/mdm mice develop a progressive muscular dystrophy, leading to death at approximately 2 months of age. We surveyed the transcriptomes of skeletal muscles from 24 day old homozygous mdm/mdm and +/+ wild-type mice, an age when MDM animals have normal passive and active tensions and sarcomeric structure. Of the 12488 genes surveyed (U74 affymetrix array), 75 genes were twofold to 30-fold differentially expressed, including (cardiac ankyrin repeat protein), ankrd2/Arpp (a protein) and MLP (muscle LIM protein), all of which associate with the titin filament system. The four genes most strongly affected (eightfold to 30-fold change) were all members of the Nkx-2.5-dependent signal pathway, and Cduanyu37 mRNA level was 30-fold elevated in MDM skeletal muscle tissues. The Cduanyu37 protein overexpressed in MDM became associated with the I-band region of the sarcomere. The mdm mutation excises the C-terminal portion of titin's N2A region, abolishing its interaction with p94/calpain-3 protease. Thus, the composition of the titin N2A protein complex is altered in MDM by incorporation of Cduanyu37 and loss of p94/calpain-3. These changes were absent from the following control tissues (1). cardiac muscles from homozygous mdm/mdm animals, (2). skeletal and cardiac muscle from heterozygous mdm/+ animals, and (3). dystrophic muscles from MDX mice. Thus, the altered composition of the titin N2A complex is specific for the titin-based skeletal muscular dystrophy in MDM.

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