Myostatin augments muscle-specific ring finger protein-1 expression through an NF-kB independent mechanism in SMAD3 null muscle.
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.
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.
Sandhya
S
Sriram
Subha
S
Subramanian
Prasanna Kumar
PK
Juvvuna
Xiaojia
X
Ge
Sudarsanareddy
S
Lokireddy
Craig Desmond
CD
McFarlane
Walter
W
Wahli
Ravi
R
Kambadur
Mridula
M
Sharma
D000818:Animals; D016466:CHO Cells; D002374:Catalase / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005979:Glutathione Peroxidase / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000378:metabolism / Q000473:pathology; D055435:Myostatin / Q000502:physiology*; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D051900:Smad3 Protein / Q000172:deficiency / Q000235:genetics*; D051742:Transcription Factor CHOP / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
C497250:Ddit3 protein, mouse; D045222:Electron Transport Chain Complex Proteins; D015850:Interleukin-6; C525912:Mstn protein, mouse; D009124:Muscle Proteins; D055435:Myostatin; D017382:Reactive Oxygen Species; C498144:Rela protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051996:Transcription Factor RelA; D000070584:Tripartite Motif Proteins; D051742:Transcription Factor CHOP; D002374:Catalase; D005979:Glutathione Peroxidase; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases