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IL-6 and Akt are involved in muscular pathogenesis in myasthenia gravis.

Maurer M, Bougoin S, Feferman T, Frenkian M, Bismuth J, Mouly V, Clairac G, Tzartos S, Fadel E, Eymard B, Fuchs S, Souroujon MC, Berrih-Aknin S - Acta Neuropathol Commun (2015)

Bottom Line: Furthermore, Akt phosphorylation in response to insulin was decreased in the presence of monoclonal anti-AChR antibodies.IL-6 is a myokine with known effects on signaling pathways such as Akt/mTOR (mammalian Target of Rapamycin).Since Akt plays a key role in multiple cellular processes, the reduced phosphorylation of Akt by the anti-AChR antibodies may have a significant impact on the muscle fatigability observed in MG patients.

View Article: PubMed Central - PubMed

Affiliation: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center UM76, Paris, F-75013, France. sonia.berrih-aknin@upmc.fr.

ABSTRACT

Introduction: Anti-acetylcholine receptor (AChR) autoantibodies target muscles in spontaneous human myasthenia gravis (MG) and its induced experimental autoimmune model MG (EAMG). The aim of this study was to identify novel functional mechanisms occurring in the muscle pathology of myasthenia.

Results: A transcriptome analysis performed on muscle tissue from MG patients (compared with healthy controls) and from EAMG rats (compared with control rats) revealed a deregulation of genes associated with the Interleukin-6 (IL-6) and Insulin-Like Growth Factor 1 (IGF-1) pathways in both humans and rats. The expression of IL-6 and its receptor IL-6R transcripts was found to be altered in muscles of EAMG rats and mice compared with control animals. In muscle biopsies from MG patients, IL-6 protein level was higher than in control muscles. Using cultures of human muscle cells, we evaluated the effects of anti-AChR antibodies on IL-6 production and on the phosphorylation of Protein Kinase B (PKB/Akt). Most MG sera and some monoclonal anti-AChR antibodies induced a significant increase in IL-6 production by human muscle cells. Furthermore, Akt phosphorylation in response to insulin was decreased in the presence of monoclonal anti-AChR antibodies.

Conclusions: Anti-AChR antibodies alter IL-6 production by muscle cells, suggesting a putative novel functional mechanism of action for the anti-AChR antibodies. IL-6 is a myokine with known effects on signaling pathways such as Akt/mTOR (mammalian Target of Rapamycin). Since Akt plays a key role in multiple cellular processes, the reduced phosphorylation of Akt by the anti-AChR antibodies may have a significant impact on the muscle fatigability observed in MG patients.

No MeSH data available.


Related in: MedlinePlus

Analysis of gene categories modified in human and rat myasthenia show similar results. Scheme of the significantly enriched Gene Ontology categories in the cellular component system. Categories with significantly enriched gene numbers determined by a hypergeometric test (http://bioinfo.vanderbilt.edu/webgestalt/) are indicated in red; categories shown in black are non-enriched. GOTM analysis demonstrated a strikingly similar tree in human and rat muscle and demonstrates the involvement of genes included in the muscle fiber category (grey boxes).
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Fig1: Analysis of gene categories modified in human and rat myasthenia show similar results. Scheme of the significantly enriched Gene Ontology categories in the cellular component system. Categories with significantly enriched gene numbers determined by a hypergeometric test (http://bioinfo.vanderbilt.edu/webgestalt/) are indicated in red; categories shown in black are non-enriched. GOTM analysis demonstrated a strikingly similar tree in human and rat muscle and demonstrates the involvement of genes included in the muscle fiber category (grey boxes).

Mentions: Transcriptome analysis was performed on both data sets, human and rats. The data were analyzed using the GOTM [21] that generates a tree-like structure and yields two types of data: 1) the subcategories presenting statistical changes and 2) the hierarchy between these different subcategories. In this representation, the downstream category is a subgroup of the upstream category. Figure 1 shows a strikingly similar tree for human and rat myasthenic muscle compared with their respective controls and suggests the involvement of genes included in the muscle fiber category in the pathology of MG (deregulated gene categories are marked in red).Figure 1


IL-6 and Akt are involved in muscular pathogenesis in myasthenia gravis.

Maurer M, Bougoin S, Feferman T, Frenkian M, Bismuth J, Mouly V, Clairac G, Tzartos S, Fadel E, Eymard B, Fuchs S, Souroujon MC, Berrih-Aknin S - Acta Neuropathol Commun (2015)

Analysis of gene categories modified in human and rat myasthenia show similar results. Scheme of the significantly enriched Gene Ontology categories in the cellular component system. Categories with significantly enriched gene numbers determined by a hypergeometric test (http://bioinfo.vanderbilt.edu/webgestalt/) are indicated in red; categories shown in black are non-enriched. GOTM analysis demonstrated a strikingly similar tree in human and rat muscle and demonstrates the involvement of genes included in the muscle fiber category (grey boxes).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4308930&req=5

Fig1: Analysis of gene categories modified in human and rat myasthenia show similar results. Scheme of the significantly enriched Gene Ontology categories in the cellular component system. Categories with significantly enriched gene numbers determined by a hypergeometric test (http://bioinfo.vanderbilt.edu/webgestalt/) are indicated in red; categories shown in black are non-enriched. GOTM analysis demonstrated a strikingly similar tree in human and rat muscle and demonstrates the involvement of genes included in the muscle fiber category (grey boxes).
Mentions: Transcriptome analysis was performed on both data sets, human and rats. The data were analyzed using the GOTM [21] that generates a tree-like structure and yields two types of data: 1) the subcategories presenting statistical changes and 2) the hierarchy between these different subcategories. In this representation, the downstream category is a subgroup of the upstream category. Figure 1 shows a strikingly similar tree for human and rat myasthenic muscle compared with their respective controls and suggests the involvement of genes included in the muscle fiber category in the pathology of MG (deregulated gene categories are marked in red).Figure 1

Bottom Line: Furthermore, Akt phosphorylation in response to insulin was decreased in the presence of monoclonal anti-AChR antibodies.IL-6 is a myokine with known effects on signaling pathways such as Akt/mTOR (mammalian Target of Rapamycin).Since Akt plays a key role in multiple cellular processes, the reduced phosphorylation of Akt by the anti-AChR antibodies may have a significant impact on the muscle fatigability observed in MG patients.

View Article: PubMed Central - PubMed

Affiliation: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center UM76, Paris, F-75013, France. sonia.berrih-aknin@upmc.fr.

ABSTRACT

Introduction: Anti-acetylcholine receptor (AChR) autoantibodies target muscles in spontaneous human myasthenia gravis (MG) and its induced experimental autoimmune model MG (EAMG). The aim of this study was to identify novel functional mechanisms occurring in the muscle pathology of myasthenia.

Results: A transcriptome analysis performed on muscle tissue from MG patients (compared with healthy controls) and from EAMG rats (compared with control rats) revealed a deregulation of genes associated with the Interleukin-6 (IL-6) and Insulin-Like Growth Factor 1 (IGF-1) pathways in both humans and rats. The expression of IL-6 and its receptor IL-6R transcripts was found to be altered in muscles of EAMG rats and mice compared with control animals. In muscle biopsies from MG patients, IL-6 protein level was higher than in control muscles. Using cultures of human muscle cells, we evaluated the effects of anti-AChR antibodies on IL-6 production and on the phosphorylation of Protein Kinase B (PKB/Akt). Most MG sera and some monoclonal anti-AChR antibodies induced a significant increase in IL-6 production by human muscle cells. Furthermore, Akt phosphorylation in response to insulin was decreased in the presence of monoclonal anti-AChR antibodies.

Conclusions: Anti-AChR antibodies alter IL-6 production by muscle cells, suggesting a putative novel functional mechanism of action for the anti-AChR antibodies. IL-6 is a myokine with known effects on signaling pathways such as Akt/mTOR (mammalian Target of Rapamycin). Since Akt plays a key role in multiple cellular processes, the reduced phosphorylation of Akt by the anti-AChR antibodies may have a significant impact on the muscle fatigability observed in MG patients.

No MeSH data available.


Related in: MedlinePlus