PMID- 20967264
OWN - NLM
STAT- MEDLINE
DCOM- 20110307
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 5
IP  - 10
DP  - 2010 Oct 12
TI  - Tumor necrosis factor-alpha regulates distinct molecular pathways and gene networks 
      in cultured skeletal muscle cells.
PG  - e13262
LID - e13262 [pii]
LID - 10.1371/journal.pone.0013262 [doi]
AB  - BACKGROUND: Skeletal muscle wasting is a debilitating consequence of large number 
      of disease states and conditions. Tumor necrosis factor-alpha (TNF-alpha) is one of the 
      most important muscle-wasting cytokine, elevated levels of which cause 
      significant muscular abnormalities. However, the underpinning molecular 
      mechanisms by which TNF-alpha causes skeletal muscle wasting are less 
      well-understood. METHODOLOGY/PRINCIPAL FINDINGS: We have used microarray, 
      quantitative real-time PCR (QRT-PCR), Western blot, and bioinformatics tools to 
      study the effects of TNF-alpha on various molecular pathways and gene networks in 
      C2C12 cells (a mouse myoblastic cell line). Microarray analyses of C2C12 myotubes 
      treated with TNF-alpha (10 ng/ml) for 18h showed differential expression of a number 
      of genes involved in distinct molecular pathways. The genes involved in nuclear 
      factor-kappa B (NF-kappaB) signaling, 26s proteasome pathway, Notch1 signaling, 
      and chemokine networks are the most important ones affected by TNF-alpha. The 
      expression of some of the genes in microarray dataset showed good correlation in 
      independent QRT-PCR and Western blot assays. Analysis of TNF-treated myotubes 
      showed that TNF-alpha augments the activity of both canonical and alternative NF-kappaB 
      signaling pathways in myotubes. Bioinformatics analyses of microarray dataset 
      revealed that TNF-alpha affects the activity of several important pathways including 
      those involved in oxidative stress, hepatic fibrosis, mitochondrial dysfunction, 
      cholesterol biosynthesis, and TGF-beta signaling. Furthermore, TNF-alpha was found to 
      affect the gene networks related to drug metabolism, cell cycle, cancer, 
      neurological disease, organismal injury, and abnormalities in myotubes. 
      CONCLUSIONS: TNF-alpha regulates the expression of multiple genes involved in various 
      toxic pathways which may be responsible for TNF-induced muscle loss in catabolic 
      conditions. Our study suggests that TNF-alpha activates both canonical and 
      alternative NF-kappaB signaling pathways in a time-dependent manner in skeletal 
      muscle cells. The study provides novel insight into the mechanisms of action of 
      TNF-alpha in skeletal muscle cells.
FAU - Bhatnagar, Shephali
AU  - Bhatnagar S
AD  - Department of Anatomical Sciences and Neurobiology, University of Louisville 
      School of Medicine, Louisville, Kentucky, United States of America.
FAU - Panguluri, Siva K
AU  - Panguluri SK
FAU - Gupta, Sanjay K
AU  - Gupta SK
FAU - Dahiya, Saurabh
AU  - Dahiya S
FAU - Lundy, Robert F
AU  - Lundy RF
FAU - Kumar, Ashok
AU  - Kumar A
LA  - eng
GR  - R01 AG029623/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Validation Study
DEP - 20101012
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (NF-kappa B)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Down-Regulation
MH  - Gene Expression Profiling
MH  - *Gene Regulatory Networks
MH  - Mice
MH  - Muscle, Skeletal/cytology/*metabolism
MH  - NF-kappa B/metabolism
MH  - Oligonucleotide Array Sequence Analysis
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction
MH  - Tumor Necrosis Factor-alpha/*physiology
MH  - Up-Regulation
PMC - PMC2953497
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2010/10/23 06:00
MHDA- 2011/03/08 06:00
PMCR- 2010/10/12
CRDT- 2010/10/23 06:00
PHST- 2010/07/09 00:00 [received]
PHST- 2010/09/14 00:00 [accepted]
PHST- 2010/10/23 06:00 [entrez]
PHST- 2010/10/23 06:00 [pubmed]
PHST- 2011/03/08 06:00 [medline]
PHST- 2010/10/12 00:00 [pmc-release]
AID - e13262 [pii]
AID - 10-PONE-RA-20888R1 [pii]
AID - 10.1371/journal.pone.0013262 [doi]
PST - epublish
SO  - PLoS One. 2010 Oct 12;5(10):e13262. doi: 10.1371/journal.pone.0013262.