Limits...
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

IL-6 and IL-6R expression is modified in muscle from animal models of MG. mRNA expression of IL-6 and IL-6R in muscles of EAMG and control CFA-immunized rats (A and B) and mice (C and D). mRNA expression levels of IL-6 (A and C) and IL-6R (B and D) were determined by Q-RT-PCR. In IL-6 transcript levels for mice, the EAMG group was separated in EAMG score with a zero-to-moderate clinical score (<6) and EAMG with a high score (>7). The clinical weakness was evaluated by weight loss, reduced grip strength, and reduced ability to hang on an inverted grid. β-Actin for rats and Rpl32 for mice were used as an inner control for normalization of IL-6 and IL-6R. The groups were compared using t-tests for significance. ANOVA was used for mice IL-6 transcripts levels (C, p = 0.0315). Post-test comparisons of groups were not individually significant, but a trend could be observed (Controls versus EAMG (0–6) p = 0.0516; EAMG (0–6) versus EAMG (7–9) p = 0.0792) ***p < 0.001; **p < 0.01; *p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: IL-6 and IL-6R expression is modified in muscle from animal models of MG. mRNA expression of IL-6 and IL-6R in muscles of EAMG and control CFA-immunized rats (A and B) and mice (C and D). mRNA expression levels of IL-6 (A and C) and IL-6R (B and D) were determined by Q-RT-PCR. In IL-6 transcript levels for mice, the EAMG group was separated in EAMG score with a zero-to-moderate clinical score (<6) and EAMG with a high score (>7). The clinical weakness was evaluated by weight loss, reduced grip strength, and reduced ability to hang on an inverted grid. β-Actin for rats and Rpl32 for mice were used as an inner control for normalization of IL-6 and IL-6R. The groups were compared using t-tests for significance. ANOVA was used for mice IL-6 transcripts levels (C, p = 0.0315). Post-test comparisons of groups were not individually significant, but a trend could be observed (Controls versus EAMG (0–6) p = 0.0516; EAMG (0–6) versus EAMG (7–9) p = 0.0792) ***p < 0.001; **p < 0.01; *p < 0.05.

Mentions: By using RT-PCR, we showed that the expression of IL-6 and IL-6R were altered in the muscles of EAMG rats and mice in comparison with control CFA-immunized animals. The expression of IL-6 was 3-fold lower in EAMG rats than in control CFA rats (Figure 2A), but about 2-fold higher in EAMG mice (Figure 2C); the expression of IL-6R was about 1.5–3-fold higher in muscles of EAMG animals than in control-CFA rats or mice (Figures 2B and D). The contradictory IL-6 results between mice and rats may be the result of the disease severity. Indeed, the rat model is more effective and all rats exhibited a severe clinical score, whereas most mice did not show more than a slight muscle strength decrease. Only three mice had a severe phenotype and their IL-6 transcript levels were very low (Figure 2C).Figure 2


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)

IL-6 and IL-6R expression is modified in muscle from animal models of MG. mRNA expression of IL-6 and IL-6R in muscles of EAMG and control CFA-immunized rats (A and B) and mice (C and D). mRNA expression levels of IL-6 (A and C) and IL-6R (B and D) were determined by Q-RT-PCR. In IL-6 transcript levels for mice, the EAMG group was separated in EAMG score with a zero-to-moderate clinical score (<6) and EAMG with a high score (>7). The clinical weakness was evaluated by weight loss, reduced grip strength, and reduced ability to hang on an inverted grid. β-Actin for rats and Rpl32 for mice were used as an inner control for normalization of IL-6 and IL-6R. The groups were compared using t-tests for significance. ANOVA was used for mice IL-6 transcripts levels (C, p = 0.0315). Post-test comparisons of groups were not individually significant, but a trend could be observed (Controls versus EAMG (0–6) p = 0.0516; EAMG (0–6) versus EAMG (7–9) p = 0.0792) ***p < 0.001; **p < 0.01; *p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: IL-6 and IL-6R expression is modified in muscle from animal models of MG. mRNA expression of IL-6 and IL-6R in muscles of EAMG and control CFA-immunized rats (A and B) and mice (C and D). mRNA expression levels of IL-6 (A and C) and IL-6R (B and D) were determined by Q-RT-PCR. In IL-6 transcript levels for mice, the EAMG group was separated in EAMG score with a zero-to-moderate clinical score (<6) and EAMG with a high score (>7). The clinical weakness was evaluated by weight loss, reduced grip strength, and reduced ability to hang on an inverted grid. β-Actin for rats and Rpl32 for mice were used as an inner control for normalization of IL-6 and IL-6R. The groups were compared using t-tests for significance. ANOVA was used for mice IL-6 transcripts levels (C, p = 0.0315). Post-test comparisons of groups were not individually significant, but a trend could be observed (Controls versus EAMG (0–6) p = 0.0516; EAMG (0–6) versus EAMG (7–9) p = 0.0792) ***p < 0.001; **p < 0.01; *p < 0.05.
Mentions: By using RT-PCR, we showed that the expression of IL-6 and IL-6R were altered in the muscles of EAMG rats and mice in comparison with control CFA-immunized animals. The expression of IL-6 was 3-fold lower in EAMG rats than in control CFA rats (Figure 2A), but about 2-fold higher in EAMG mice (Figure 2C); the expression of IL-6R was about 1.5–3-fold higher in muscles of EAMG animals than in control-CFA rats or mice (Figures 2B and D). The contradictory IL-6 results between mice and rats may be the result of the disease severity. Indeed, the rat model is more effective and all rats exhibited a severe clinical score, whereas most mice did not show more than a slight muscle strength decrease. Only three mice had a severe phenotype and their IL-6 transcript levels were very low (Figure 2C).Figure 2

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