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Involvement of adiponectin in the pathogenesis of dystrophinopathy.

Abou-Samra M, Lecompte S, Schakman O, Noel L, Many MC, Gailly P, Brichard SM - Skelet Muscle (2015)

Bottom Line: Eventually, primary cultures of human myotubes were used.These beneficial effects of ApN were recapitulated in human myotubes.Adiponectin proves to be an extremely powerful hormone capable of protecting the skeletal muscle against inflammation and injury, thereby offering novel therapeutic perspectives for dystrophinopathies.

View Article: PubMed Central - PubMed

Affiliation: Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Catholic University of Louvain, 1200 Brussels, Belgium.

ABSTRACT

Background: The hormone adiponectin (ApN) is decreased in the metabolic syndrome, where it plays a key pathogenic role. ApN also exerts some anti-inflammatory effects on skeletal muscles in mice exposed to acute or chronic inflammation. Here, we investigate whether ApN could be sufficiently potent to counteract a severe degenerative muscle disease, with an inflammatory component such as Duchenne muscular dystrophy (DMD).

Methods: Mdx mice (a DMD model caused by dystrophin mutation) were crossed with mice overexpressing ApN in order to generate mdx-ApN mice; only littermates were used. Different markers of inflammation/oxidative stress and components of signaling pathways were studied. Global force was assessed by in vivo functional tests, and muscle injury with Evans Blue Dye (EBD). Eventually, primary cultures of human myotubes were used.

Results: Circulating ApN was markedly diminished in mdx mice. Replenishment of ApN strikingly reduced muscle inflammation, oxidative stress, and enhanced the expression of myogenic differentiation markers along with that of utrophin A (a dystrophin analog) in mdx-ApN mice. Accordingly, mdx-ApN mice exhibited higher global force and endurance as well as decreased muscle damage as quantified by curtailed extravasation of EBD in myofibers. These beneficial effects of ApN were recapitulated in human myotubes. ApN mediates its protection via the adiponectin receptor 1 (AdipoR1, the main ApN receptor in muscle) and the AMPK-SIRT1-PGC-1α signaling pathway, leading to downregulation of the nuclear factor kappa B (NF-κB) and inflammatory genes, together with upregulation of utrophin.

Conclusions: Adiponectin proves to be an extremely powerful hormone capable of protecting the skeletal muscle against inflammation and injury, thereby offering novel therapeutic perspectives for dystrophinopathies.

No MeSH data available.


Related in: MedlinePlus

Inflammation in the skeletal muscle of mdx mice. Successive sections of Tibialis anterior muscles from 8-week-old mdx and mdx-ApN mice were stained for CD68, TNFα, and IL-1β. Representative sections for six mice per group are shown. Scale bar = 250 μm
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Fig3: Inflammation in the skeletal muscle of mdx mice. Successive sections of Tibialis anterior muscles from 8-week-old mdx and mdx-ApN mice were stained for CD68, TNFα, and IL-1β. Representative sections for six mice per group are shown. Scale bar = 250 μm

Mentions: When compared to WT mice, myofibers from tibialis anterior of mdx mice displayed a strong immunolabeling for PRDX3/5, two markers of oxidative stress, and for HNE, a lipid peroxidation product (Fig. 1). Quantification of this immunolabeling showed that the extent of DAB staining within myofibers was ~7.5- to 9.5-fold higher in mdx than in WT mice (see Fig. 2a–c). Qualitatively similar results were observed for TNFα and for IL-1β, two pro-inflammatory cytokines (Fig. 1), with an extent of DAB staining being 11- and 6-fold greater in mdx than in WT mice, respectively (Fig. 2d, e). In addition, a massive infiltration of both T lymphocytes (immunolabeling for CD3) and macrophages (CD68, a marker of the pro-inflammatory M1 phenotype; [25]) was observed in mdx mice, but not in WT mice (Fig. 1 and Fig. 2f, g). All these indicators of oxidative stress and inflammation were remarkably reduced in mdx-ApN mice (Figs. 1 and 2). Serial muscle cross-sections revealed that both myocytes and macrophages contribute to the production of pro-inflammatory cytokines. In mdx mice, areas that were positive for C68 were negative for TNFα, while this cytokine was abundant within the myocytes. A reverse pattern of expression was however observed for IL-1β, which was mainly produced by macrophages and less by myocytes (Fig. 3). Remarkably, gene expression of IL-10, an anti-inflammatory cytokine that activates the M2 macrophage phenotype [25] was also markedly increased in mdx-ApN mice (Fig. 2h). Taken together, these data suggest that ApN is able to strongly defend the skeletal muscle against excessive inflammatory reactions and oxidative stress.Fig. 1


Involvement of adiponectin in the pathogenesis of dystrophinopathy.

Abou-Samra M, Lecompte S, Schakman O, Noel L, Many MC, Gailly P, Brichard SM - Skelet Muscle (2015)

Inflammation in the skeletal muscle of mdx mice. Successive sections of Tibialis anterior muscles from 8-week-old mdx and mdx-ApN mice were stained for CD68, TNFα, and IL-1β. Representative sections for six mice per group are shown. Scale bar = 250 μm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4528853&req=5

Fig3: Inflammation in the skeletal muscle of mdx mice. Successive sections of Tibialis anterior muscles from 8-week-old mdx and mdx-ApN mice were stained for CD68, TNFα, and IL-1β. Representative sections for six mice per group are shown. Scale bar = 250 μm
Mentions: When compared to WT mice, myofibers from tibialis anterior of mdx mice displayed a strong immunolabeling for PRDX3/5, two markers of oxidative stress, and for HNE, a lipid peroxidation product (Fig. 1). Quantification of this immunolabeling showed that the extent of DAB staining within myofibers was ~7.5- to 9.5-fold higher in mdx than in WT mice (see Fig. 2a–c). Qualitatively similar results were observed for TNFα and for IL-1β, two pro-inflammatory cytokines (Fig. 1), with an extent of DAB staining being 11- and 6-fold greater in mdx than in WT mice, respectively (Fig. 2d, e). In addition, a massive infiltration of both T lymphocytes (immunolabeling for CD3) and macrophages (CD68, a marker of the pro-inflammatory M1 phenotype; [25]) was observed in mdx mice, but not in WT mice (Fig. 1 and Fig. 2f, g). All these indicators of oxidative stress and inflammation were remarkably reduced in mdx-ApN mice (Figs. 1 and 2). Serial muscle cross-sections revealed that both myocytes and macrophages contribute to the production of pro-inflammatory cytokines. In mdx mice, areas that were positive for C68 were negative for TNFα, while this cytokine was abundant within the myocytes. A reverse pattern of expression was however observed for IL-1β, which was mainly produced by macrophages and less by myocytes (Fig. 3). Remarkably, gene expression of IL-10, an anti-inflammatory cytokine that activates the M2 macrophage phenotype [25] was also markedly increased in mdx-ApN mice (Fig. 2h). Taken together, these data suggest that ApN is able to strongly defend the skeletal muscle against excessive inflammatory reactions and oxidative stress.Fig. 1

Bottom Line: Eventually, primary cultures of human myotubes were used.These beneficial effects of ApN were recapitulated in human myotubes.Adiponectin proves to be an extremely powerful hormone capable of protecting the skeletal muscle against inflammation and injury, thereby offering novel therapeutic perspectives for dystrophinopathies.

View Article: PubMed Central - PubMed

Affiliation: Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Catholic University of Louvain, 1200 Brussels, Belgium.

ABSTRACT

Background: The hormone adiponectin (ApN) is decreased in the metabolic syndrome, where it plays a key pathogenic role. ApN also exerts some anti-inflammatory effects on skeletal muscles in mice exposed to acute or chronic inflammation. Here, we investigate whether ApN could be sufficiently potent to counteract a severe degenerative muscle disease, with an inflammatory component such as Duchenne muscular dystrophy (DMD).

Methods: Mdx mice (a DMD model caused by dystrophin mutation) were crossed with mice overexpressing ApN in order to generate mdx-ApN mice; only littermates were used. Different markers of inflammation/oxidative stress and components of signaling pathways were studied. Global force was assessed by in vivo functional tests, and muscle injury with Evans Blue Dye (EBD). Eventually, primary cultures of human myotubes were used.

Results: Circulating ApN was markedly diminished in mdx mice. Replenishment of ApN strikingly reduced muscle inflammation, oxidative stress, and enhanced the expression of myogenic differentiation markers along with that of utrophin A (a dystrophin analog) in mdx-ApN mice. Accordingly, mdx-ApN mice exhibited higher global force and endurance as well as decreased muscle damage as quantified by curtailed extravasation of EBD in myofibers. These beneficial effects of ApN were recapitulated in human myotubes. ApN mediates its protection via the adiponectin receptor 1 (AdipoR1, the main ApN receptor in muscle) and the AMPK-SIRT1-PGC-1α signaling pathway, leading to downregulation of the nuclear factor kappa B (NF-κB) and inflammatory genes, together with upregulation of utrophin.

Conclusions: Adiponectin proves to be an extremely powerful hormone capable of protecting the skeletal muscle against inflammation and injury, thereby offering novel therapeutic perspectives for dystrophinopathies.

No MeSH data available.


Related in: MedlinePlus