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Myostatin augments muscle-specific ring finger protein-1 expression through an NF-kB independent mechanism in SMAD3 null muscle.

Authors
  • Sriram, Sandhya1
  • Subramanian, Subha
  • Juvvuna, Prasanna Kumar
  • Ge, Xiaojia
  • Lokireddy, Sudarsanareddy
  • McFarlane, Craig Desmond
  • Wahli, Walter
  • Kambadur, Ravi
  • Sharma, Mridula
  • 1 Division of Molecular Genetics and Cell Biology (S.Sr., S.Su., R.K.), School of Biological Sciences, Nanyang Technological University, Singapore 637551; Department of Biochemistry (P.K.J., M.S.) YLLSoM, National University of Singapore, MD6, Level 14 S Core, Singapore 117599; Growth, Development and Metabolism Program (X.G., C.D.M., R.K.), Singapore Institute of Clinical Sciences, Brenner Centre for Molecular Medicine, Singapore 117609; Department of Cell Biology (S.L.), Harvard Medical School, Boston, Massachusetts 02115-5730; and Center for Integrative Genomics (W.W.), University of Lausanne, Lausanne, Switzerland. , (Switzerland)
Type
Published Article
Journal
Molecular Endocrinology
Publisher
The Endocrine Society
Publication Date
March 2014
Volume
28
Issue
3
Pages
317–330
Identifiers
DOI: 10.1210/me.2013-1179
PMID: 24438338
Source
Medline
License
Unknown

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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