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Role of IGF-I and the TNFα/NF-κB pathway in the induction of muscle atrogenes by acute inflammation.
- Source :
-
American journal of physiology. Endocrinology and metabolism [Am J Physiol Endocrinol Metab] 2012 Sep 15; Vol. 303 (6), pp. E729-39. Date of Electronic Publication: 2012 Jun 26. - Publication Year :
- 2012
-
Abstract
- Several catabolic states (sepsis, cancer, etc.) associated with acute inflammation are characterized by a loss of skeletal muscle due to accelerated proteolysis. The main proteolytic systems involved are the autophagy and the ubiquitin-proteasome (UPS) pathways. Among the signaling pathways that could mediate proteolysis induced by acute inflammation, the transcription factor NF-κB, induced by TNFα, and the transcription factor forkhead box O (FOXO), induced by glucocorticoids (GC) and inhibited by IGF-I, are likely to play a key role. The aim of this study was to identify the nature of the molecular mediators responsible for the induction of these muscle proteolytic systems in response to acute inflammation caused by LPS injection. LPS injection robustly stimulated the expression of several components of the autophagy and the UPS pathways in the skeletal muscle. This induction was associated with a rapid increase of circulating levels of TNFα together with a muscular activation of NF-κB followed by a decrease in circulating and muscle levels of IGF-I. Neither restoration of circulating IGF-I nor restoration of muscle IGF-I levels prevented the activation of autophagy and UPS genes by LPS. The inhibition of TNFα production and muscle NF-κB activation, respectively by using pentoxifilline and a repressor of NF-κB, did not prevent the activation of autophagy and UPS genes by LPS. Finally, inhibition of GC action with RU-486 blunted completely the activation of these atrogenes by LPS. In conclusion, we show that increased GC production plays a more crucial role than decreased IGF-I and increased TNFα/NF-κB pathway for the induction of the proteolytic systems caused by acute inflammation.
- Subjects :
- Animals
Autophagy drug effects
Glucocorticoids adverse effects
Glucocorticoids antagonists & inhibitors
I-kappa B Proteins genetics
I-kappa B Proteins metabolism
Insulin-Like Growth Factor I analysis
Insulin-Like Growth Factor I genetics
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Muscle Proteins antagonists & inhibitors
Muscle Proteins genetics
Muscle, Skeletal drug effects
Muscle, Skeletal immunology
Muscular Atrophy blood
Muscular Atrophy immunology
Muscular Atrophy prevention & control
NF-kappa B antagonists & inhibitors
Proteasome Endopeptidase Complex drug effects
Proteasome Endopeptidase Complex genetics
Proteasome Endopeptidase Complex metabolism
Proteolysis drug effects
RNA, Messenger metabolism
Random Allocation
Rats
Rats, Wistar
Tumor Necrosis Factor-alpha antagonists & inhibitors
Tumor Necrosis Factor-alpha blood
Tumor Necrosis Factor-alpha genetics
Insulin-Like Growth Factor I metabolism
Muscle Proteins metabolism
Muscle, Skeletal metabolism
Muscular Atrophy metabolism
NF-kappa B metabolism
Tumor Necrosis Factor-alpha metabolism
Up-Regulation drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1555
- Volume :
- 303
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Endocrinology and metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 22739109
- Full Text :
- https://doi.org/10.1152/ajpendo.00060.2012