Conditional expression of mutant M-line titins results in cardiomyopathy with altered sarcomere structure.
Titin is a giant protein responsible for muscle elasticity and provides a scaffold for several sarcomeric proteins, including the novel titin-binding protein MURF-1, which binds near the titin M-line region. Another unique feature of titin is the presence of a serine/threonine kinase-like domain at the edge of the M-line region of the sarcomere, for which no physiological catalytic function has yet been shown. To investigate the role(s) of the titin M-line segment, we have conditionally deleted the exons MEx1 and MEx2 (encoding the kinase domain plus flanking sequences) at different stages of embryonic development. Our data demonstrate an important role for MEx1 and MEx2 in early cardiac development (embryonic lethality) as well as postnatally when disruption of M-line titin leads to muscle weakness and death at approximately 5 weeks of age. Myopathic changes include pale M-lines devoid of MURF-1, and gradual sarcomeric disassembly. The animal model presented here indicates a critical role for the M-line region of titin in maintaining the structural integrity of the sarcomere.
Gotthardt
Michael
M
Department of Molecular Genetics, University of Texas, Southwestern Medical Center, Dallas, Texas 75390, USA. Gotthard@vetmed.wsu.edu
Hammer
Robert E
RE
Hübner
Norbert
N
Monti
Jan
J
Witt
Christian C
CC
McNabb
Mark
M
Richardson
James A
JA
Granzier
Henk
H
Labeit
Siegfried
S
Herz
Joachim
J
D000199:Actins / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology; D022202:Chromosomes, Artificial, Bacterial; D003001:Cloning, Molecular; D064211:Connectin; D004548:Elasticity; D005786:Gene Expression Regulation; D008285:Major Histocompatibility Complex; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology; D018995:Myosin Heavy Chains / Q000235:genetics; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011995:Recombination, Genetic; D012518:Sarcomeres / Q000473:pathology* / Q000648:ultrastructure; D013234:Stem Cells / Q000502:physiology
D000199:Actins; D064211:Connectin; D009124:Muscle Proteins; D011494:Protein Kinases; D018995:Myosin Heavy Chains