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The Journal of General Physiology (1)
The Yale Journal of Biology and Medicine (1)
Labeit, Siegfried (2)
Smith, John E. (2)
Beeson, Paul B. (1)
Bondy, Philip K. (1)
Buck, Danielle (1)
Chung, Charles S (1)
Chung, Charles S. (1)
Donnelly, Richard C. (1)
Granzier, Henk L (1)
Granzier, Henk L. (1)
Guo, Caiying (1)
Hidalgo, Carlos G (1)
Hutchinson, Kirk R (1)
Luo, Xiuju (1)
Methawasin, Mei (1)
Ono, Yasuko (1)
Saripalli, Chandra (1)
Smith, John E (1)
Sorimachi, Hiroyuki (1)
Year of Publication
Removal of immunoglobulin-like domains from titin’s spring segment alters titin splicing in mouse skeletal muscle and causes myopathy
Chung, Charles S.
Granzier, Henk L.
The Journal of General Physiology
Changes in titin splicing resulting in decreased size and increased stiffness lead to pathological changes in skeletal muscle.
Titin is a molecular spring that determines the passive stiffness of muscle cells. Changes in titin’s stiffness occur in various myopathies, but whether these are a cause or an effect of the disease is unknown. We studied a novel mouse model in which titin’s stiffness was slightly increased by deleting nine immunoglobulin (Ig)-like domains from titin’s constitutively expressed proximal tandem Ig segment (IG KO). KO mice displayed mild kyphosis, a phenotype commonly associated with skeletal muscle myopathy. Slow muscles were atrophic with alterations in myosin isoform expression; functional studies in soleus muscle revealed a reduced specific twitch force. Exon expression analysis showed that KO mice underwent additional changes in titin splicing to yield smaller than expected titin isoforms that were much stiffer than expected. Additionally, splicing occurred in the PEVK region of titin, a finding confirmed at the protein level. The titin-binding protein Ankrd1 was highly increased in the IG KO, but this did not play a role in generating small titin isoforms because titin expression was unaltered in IG KO mice crossed with Ankrd1-deficient mice. In contrast, the splicing factor RBM20 (RNA-binding motif 20) was also significantly increased in IG KO mice, and additional differential splicing was reversed in IG KO mice crossed with a mouse with reduced RBM20 activity. Thus, increasing titin’s stiffness triggers pathological changes in skeletal muscle, with an important role played by RBM20.
Shortening of Titin’s Elastic Tandem Ig Segment Leads to Diastolic Dysfunction
Chung, Charles S
Hutchinson, Kirk R
Hidalgo, Carlos G
Granzier, Henk L
Diastolic dysfunction is a poorly understood but clinically pervasive syndrome that is characterized by increased diastolic stiffness. Titin is the main determinant of cellular passive stiffness. However, the physiological role that titin’s tandem Ig segment plays in stiffness generation and whether shortening this segment is sufficient to cause diastolic dysfunction needs to be established.
METHODS AND RESULTS
We generated a mouse model in which nine immunoglobulin (Ig)-like domains (Ig3-11) were deleted from the proximal tandem Ig segment of titin’s spring region (IG KO). Exon microarray analysis revealed no adaptations in titin splicing, while novel phospho-specific antibodies did not detect changes in titin phosphorylation. Passive myocyte stiffness was increased in the IG KO and immunoelectron microscopy revealed increased extension of the remaining titin spring segments as the sole likely underlying mechanism. Diastolic stiffness was increased at the tissue and organ levels, with no consistent changes in ECM composition or ECM-based passive stiffness, supporting a titin-based mechanism for in-vivo diastolic dysfunction. Additionally, IG KO mice have a reduced exercise tolerance, a phenotype often associated with diastolic dysfunction.
Increased titin-based passive stiffness is sufficient to cause diastolic dysfunction with exercise intolerance.
Passive stiffness; elasticity; extracellular matrix; exercise; hypertrophy
Panel Discussion: Moral Issues in Clinical Research ‡
Beeson, Paul B.
Bondy, Philip K.
Donnelly, Richard C.
The Yale Journal of Biology and Medicine
Results 1-3 (3)
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