Myostatin Augments Muscle-Specific Ring Finger Protein-1 Expression Through an NF-kB Independent Mechanism in SMAD3 Null Muscle

Myostatin Augments Muscle-Specific Ring Finger Protein-1 Expression Through an NF-kB Independent Mechanism in SMAD3 Null Muscle
Title:
Myostatin Augments Muscle-Specific Ring Finger Protein-1 Expression Through an NF-kB Independent Mechanism in SMAD3 Null Muscle
Other Titles:
Molecular Endocrinology
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Publication Date:
17 January 2014
Citation:
Abstract:
Smad (Sma and Mad-related protein) 2/3 are downstream signaling molecules for TGF-β and myostatin (Mstn). Recently, Mstn was shown to induce reactive oxygen species (ROS) in skeletal muscle via canonical Smad3, nuclear factor-κB, and TNF-α 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-κB (p65) signaling but due to activated p38, ERK MAPK signaling and enhanced IL-6 levels. Consequently, TNF-α, 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.
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PublisherCopyrights
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ISSN:
0888-8809
1944-9917
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