|
2009 Southern Regional Meeting Abstracts
Session: Joint Plenary Poster Session and Reception
Differential Regulation of Ubiquitin ligases Atrogin-1 and MuRF-1 in Angiotensin II-Mediated Skeletal Muscle Atrophy
Yoshida T, Semprun-Prieto L, Sukhanov S, Delafontaine P. Tulane University School of Medicine, New Orleans, LA.
Purpose of Study: Advanced congestive heart failure is associated with activation of the renin-angiotensin system and skeletal muscle atrophy. Angiotensin II (Ang II) infusion in mice produces cachexia secondarily to increased muscle proteolysis and also decreased levels of circulating and skeletal muscle IGF-1. Two E3 ubiquitin ligase genes Atrogin-1 and MuRF-1 are known to be upregulated in skeletal muscles of Ang II-infused animals and are important in mediating skeletal muscle proteolysis via the ubiquitin-proteasome system (UPS). The purpose of this study is to determine mechanisms linking Atrogin-1 and MuRF-1 expression and IGF-1 signaling.
Methods Used: Time-course dependent expression of Atrogin-1, MuRF-1, IGF-1 and IGF-1 receptor (IGF1R) was analyzed in skeletal muscles of Ang II infused mice by quantitative RT-PCR.
Summary of Results: Expression of Atrogin-1 and MuRF-1 were elevated one day after the initiation of Ang II-infusion (4.92 ± 0.86 and 7.82 ± 2.02 fold, respectively) and the expression levels gradually decreased on day 4 and day 7. On the other hand, the expression level of IGF-1 was not changed on day 1 and day 4, whereas a significant reduction (0.50 ± 0.09 fold) was observed on day 7. The expression of IGF1R was increased on day 1 and day 4 (1.32 ± 0.08 and 1.36 ± 0.09 fold, respectively), and returned to basal levels on day 7. Contrary to wild-type (WT) mice, there was no significant reduction of skeletal muscle weight in mice overexpressing IGF-1 specifically in skeletal muscle (MLC-IGF-1 mice) infused with Ang II. In skeletal muscles of MLC-IGF-1 mice, the basal and Ang II-induced expression of Atrogin-1 was significantly repressed compared to WT mice. On the other hand, basal expression level of MuRF-1 in skeletal muscles of MLC-IGF-1 mice was not different from WT animals. Furthermore, after Ang II-infusion, MuRF-1 expression was upregulated both in WT and MLC-IGF-1 mice.
Conclusions: These data demonstrate that the expression of Atrogin-1 and MuRF-1 is differentially regulated in skeletal muscles of Ang II infused mice. IGF-1 prevention of Ang II induced atrophy is mediated via the ability of IGF-1 to repress Atrogin-1 expression, rather than MuRF-1 expression.
|
