Abstract
Background: Titin is an elastic sarcomeric filament that has been proposed to play a key role in mechanosensing and trophicity of muscle. However, evidence for this proposal is scarce due to the lack of appropriate experimental models to directly test the role of titin in mechanosensing. Methods: We used unilateral diaphragm denervation (UDD) in mice, an in vivo model in which the denervated hemidiaphragm is passively stretched by the contralateral, innervated hemidiaphragm and hypertrophy rapidly occurs. Results: In wildtype mice, the denervated hemidiaphragm mass increased 48 ± 3% after 6 days of UDD, due to the addition of both sarcomeres in series and in parallel. To test whether titin stiffness modulates the hypertrophy response, RBM20ΔRRM and TtnΔIAjxn mouse models were used, with decreased and increased titin stiffness, respectively. RBM20ΔRRM mice (reduced stiffness) showed a 20 ± 6% attenuated hypertrophy response, whereas the TtnΔIAjxn mice (increased stiffness) showed an 18 ± 8% exaggerated response after UDD. Thus, muscle hypertrophy scales with titin stiffness. Protein expression analysis revealed that titin-binding proteins implicated previously in muscle trophicity were induced during UDD, MARP1 & 2, FHL1, and MuRF1. Conclusions: Titin functions as a mechanosensor that regulates muscle trophicity.
| Original language | English (US) |
|---|---|
| Journal | Journal of Cachexia, Sarcopenia and Muscle |
| DOIs | |
| State | Accepted/In press - Jan 1 2018 |
Fingerprint
Keywords
- Denervation
- Diaphragm
- Hypertrophy
- Mechanosensing
- Muscle stretch
- Titin
ASJC Scopus subject areas
- Biophysics
- Applied Microbiology and Biotechnology
- Orthopedics and Sports Medicine
- Physiology (medical)
Cite this
Titin-based mechanosensing modulates muscle hypertrophy. / van der Pijl, Robbert; Strom, Joshua; Conijn, Stefan; Lindqvist, Johan; Labeit, Siegfried; Granzier, Hendrikus "Henk"; Ottenheijm, Coen.
In: Journal of Cachexia, Sarcopenia and Muscle, 01.01.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Titin-based mechanosensing modulates muscle hypertrophy
AU - van der Pijl, Robbert
AU - Strom, Joshua
AU - Conijn, Stefan
AU - Lindqvist, Johan
AU - Labeit, Siegfried
AU - Granzier, Hendrikus "Henk"
AU - Ottenheijm, Coen
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Background: Titin is an elastic sarcomeric filament that has been proposed to play a key role in mechanosensing and trophicity of muscle. However, evidence for this proposal is scarce due to the lack of appropriate experimental models to directly test the role of titin in mechanosensing. Methods: We used unilateral diaphragm denervation (UDD) in mice, an in vivo model in which the denervated hemidiaphragm is passively stretched by the contralateral, innervated hemidiaphragm and hypertrophy rapidly occurs. Results: In wildtype mice, the denervated hemidiaphragm mass increased 48 ± 3% after 6 days of UDD, due to the addition of both sarcomeres in series and in parallel. To test whether titin stiffness modulates the hypertrophy response, RBM20ΔRRM and TtnΔIAjxn mouse models were used, with decreased and increased titin stiffness, respectively. RBM20ΔRRM mice (reduced stiffness) showed a 20 ± 6% attenuated hypertrophy response, whereas the TtnΔIAjxn mice (increased stiffness) showed an 18 ± 8% exaggerated response after UDD. Thus, muscle hypertrophy scales with titin stiffness. Protein expression analysis revealed that titin-binding proteins implicated previously in muscle trophicity were induced during UDD, MARP1 & 2, FHL1, and MuRF1. Conclusions: Titin functions as a mechanosensor that regulates muscle trophicity.
AB - Background: Titin is an elastic sarcomeric filament that has been proposed to play a key role in mechanosensing and trophicity of muscle. However, evidence for this proposal is scarce due to the lack of appropriate experimental models to directly test the role of titin in mechanosensing. Methods: We used unilateral diaphragm denervation (UDD) in mice, an in vivo model in which the denervated hemidiaphragm is passively stretched by the contralateral, innervated hemidiaphragm and hypertrophy rapidly occurs. Results: In wildtype mice, the denervated hemidiaphragm mass increased 48 ± 3% after 6 days of UDD, due to the addition of both sarcomeres in series and in parallel. To test whether titin stiffness modulates the hypertrophy response, RBM20ΔRRM and TtnΔIAjxn mouse models were used, with decreased and increased titin stiffness, respectively. RBM20ΔRRM mice (reduced stiffness) showed a 20 ± 6% attenuated hypertrophy response, whereas the TtnΔIAjxn mice (increased stiffness) showed an 18 ± 8% exaggerated response after UDD. Thus, muscle hypertrophy scales with titin stiffness. Protein expression analysis revealed that titin-binding proteins implicated previously in muscle trophicity were induced during UDD, MARP1 & 2, FHL1, and MuRF1. Conclusions: Titin functions as a mechanosensor that regulates muscle trophicity.
KW - Denervation
KW - Diaphragm
KW - Hypertrophy
KW - Mechanosensing
KW - Muscle stretch
KW - Titin
UR - http://www.scopus.com/inward/record.url?scp=85050794709&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050794709&partnerID=8YFLogxK
U2 - 10.1002/jcsm.12319
DO - 10.1002/jcsm.12319
M3 - Article
JO - AMB Express
JF - AMB Express
SN - 2191-0855
ER -