TY - JOUR
T1 - Tuning passive mechanics through differential splicing of titin during skeletal muscle development
AU - Ottenheijm, Coen A.C.
AU - Knottnerus, Anna M.
AU - Buck, Danielle
AU - Luo, Xiuju
AU - Greer, Kevin
AU - Hoying, Adam
AU - Labeit, Siegfried
AU - Granzier, Henk
N1 - Funding Information:
This work was supported by a Rubicon postdoctoral grant from the Dutch Organization for Scientific Research (C.O.), and by the National Institutes of Health (HL062881 and HL084579 to H.G.).
PY - 2009/10/21
Y1 - 2009/10/21
N2 - During postnatal development, major changes in mechanical properties of skeletal muscle occur. We investigated passive properties of skeletal muscle in mice and rabbits that varied in age from 1 day to ∼1 year. Neonatal skeletal muscle expressed large titin isoforms directly after birth, followed by a gradual switch toward progressively smaller isoforms that required weeks-to-months to be completed. This suggests an extremely high plasticity of titin splicing during skeletal muscle development. Titin exon microarray analysis showed increased expression of a large group of exons in neonatal muscle, when compared to adult muscle transcripts, with the majority of upregulated exons coding for the elastic proline-glutamate-valine-lysine (PEVK) region of titin. Protein analysis supported expression of a significantly larger PEVK segment in neonatal muscle. In line with these findings, we found >50% lower titin-based passive stiffness of neonatal muscle when compared to adult muscle. Inhibiting 3,5,3′-tri-iodo-L-thyronine and 3,5,3′,5′- tetra-iodo-L-thyronine secretion did not alter isoform switching, suggesting no major role for thyroid hormones in regulating differential titin splicing during postnatal development. In summary, our work shows that stiffening of skeletal muscle during postnatal development occurs through a decrease in titin isoform size, due mainly to a marked restructuring of the PEVK region of titin.
AB - During postnatal development, major changes in mechanical properties of skeletal muscle occur. We investigated passive properties of skeletal muscle in mice and rabbits that varied in age from 1 day to ∼1 year. Neonatal skeletal muscle expressed large titin isoforms directly after birth, followed by a gradual switch toward progressively smaller isoforms that required weeks-to-months to be completed. This suggests an extremely high plasticity of titin splicing during skeletal muscle development. Titin exon microarray analysis showed increased expression of a large group of exons in neonatal muscle, when compared to adult muscle transcripts, with the majority of upregulated exons coding for the elastic proline-glutamate-valine-lysine (PEVK) region of titin. Protein analysis supported expression of a significantly larger PEVK segment in neonatal muscle. In line with these findings, we found >50% lower titin-based passive stiffness of neonatal muscle when compared to adult muscle. Inhibiting 3,5,3′-tri-iodo-L-thyronine and 3,5,3′,5′- tetra-iodo-L-thyronine secretion did not alter isoform switching, suggesting no major role for thyroid hormones in regulating differential titin splicing during postnatal development. In summary, our work shows that stiffening of skeletal muscle during postnatal development occurs through a decrease in titin isoform size, due mainly to a marked restructuring of the PEVK region of titin.
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U2 - 10.1016/j.bpj.2009.07.041
DO - 10.1016/j.bpj.2009.07.041
M3 - Article
C2 - 19843460
AN - SCOPUS:70449124198
SN - 0006-3495
VL - 97
SP - 2277
EP - 2286
JO - Biophysical Journal
JF - Biophysical Journal
IS - 8
ER -