Muscle atrophy in titin M-line deficient mice.
We investigated the response to deletion of the titin M-line region in striated muscle, using a titin knockout model and a range of techniques that include histology, in situ hybridization, electron microscopy, and 2D gel analysis. We found that the loss of titin's kinase domain and binding sites for myomesin and MURF-1 causes structural changes in the sarcomere that proceed from the M-line to the Z-disc and ultimately result in disassembly of the sarcomere. Disassembly goes along with central localization of nuclei (a hallmark for muscular dystrophy), up-regulation of heat-shock proteins, and induction of proteasome activity. While fiber type composition does not change in soleus and extensor digitorum longus muscle, fiber size is reduced. Animals die from complications of muscle atrophy at five weeks of age. In addition to the structural importance of the titin M-line region in any striated muscle, our data show how differences in M-line composition between heart and skeletal muscle affect sarcomere stability and function.
Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, WA 99164-6520, USA.
J
J
Peng
K
K
Raddatz
S
S
Labeit
H
H
Granzier
M
M
Gotthardt
D000818:Animals; D064211:Connectin; D015180:Electrophoresis, Gel, Two-Dimensional; D005091:Exons / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D006360:Heat-Shock Proteins / Q000378:metabolism; D017403:In Situ Hybridization; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008854:Microscopy, Electron; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism / Q000473:pathology; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009133:Muscular Atrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000172:deficiency* / Q000235:genetics; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure
D064211:Connectin; D006360:Heat-Shock Proteins; D009124:Muscle Proteins; D020033:Protein Isoforms; D011494:Protein Kinases; D046988:Proteasome Endopeptidase Complex