| First Author | Sriram S | Year | 2014 |
| Journal | Mol Endocrinol | Volume | 28 |
| Issue | 3 | Pages | 317-30 |
| PubMed ID | 24438338 | Mgi Jnum | J:212349 |
| Mgi Id | MGI:5578688 | Doi | 10.1210/me.2013-1179 |
| Citation | Sriram S, et al. (2014) Myostatin augments muscle-specific ring finger protein-1 expression through an NF-kB independent mechanism in SMAD3 null muscle. Mol Endocrinol 28(3):317-30 |
| abstractText | Smad (Sma and Mad-related protein) 2/3 are downstream signaling molecules for TGF-beta and myostatin (Mstn). Recently, Mstn was shown to induce reactive oxygen species (ROS) in skeletal muscle via canonical Smad3, nuclear factor-kappaB, and TNF-alpha pathway. However, mice lacking Smad3 display skeletal muscle atrophy due to increased Mstn levels. Hence, our aims were first to investigate whether Mstn induced muscle atrophy in Smad3(-/-) mice by increasing ROS and second to delineate Smad3-independent signaling mechanism for Mstn-induced ROS. Herein we show that Smad3(-/-) mice have increased ROS levels in skeletal muscle, and inactivation of Mstn in these mice partially ablates the oxidative stress. Furthermore, ROS induction by Mstn in Smad3(-/-) muscle was not via nuclear factor-kappaB (p65) signaling but due to activated p38, ERK MAPK signaling and enhanced IL-6 levels. Consequently, TNF-alpha, nicotinamide adenine dinucleotide phosphate oxidase, and xanthine oxidase levels were up-regulated, which led to an increase in ROS production in Smad3(-/-) skeletal muscle. The exaggerated ROS in the Smad3(-/-) muscle potentiated binding of C/EBP homology protein transcription factor to MuRF1 promoter, resulting in enhanced MuRF1 levels leading to muscle atrophy. |
