Limits...
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

Effects of adiponectin on markers of the myogenic program in mdx mice. The expression of MyoD (a) and Myf5 (b), two myogenic regulatory factors, was analyzed by Western blotting in tibialis anterior muscles from the three groups of mice. Levels of each marker were normalized to actin levels. mRNA levels of Mrf4 (c) and myogenin (d), two markers of muscle differentiation. e mRNA levels of Myh3 (eMyHC), a marker of skeletal muscle regeneration. mRNA levels were normalized to cyclophilin and the subsequent ratios were presented as relative expression compared with WT values. fTibialis anterior sections stained with hematoxylin-erythrosin-safran. Scale bar = 100 μm. g The percentage of muscle fibers with central nuclei was counted. Results are means ± SD; n = 6 mice per group. **p < 0.01; ***p < 0.001 vs. WT; ##p < 0.01; ###p < 0.001 vs. mdx mice
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Effects of adiponectin on markers of the myogenic program in mdx mice. The expression of MyoD (a) and Myf5 (b), two myogenic regulatory factors, was analyzed by Western blotting in tibialis anterior muscles from the three groups of mice. Levels of each marker were normalized to actin levels. mRNA levels of Mrf4 (c) and myogenin (d), two markers of muscle differentiation. e mRNA levels of Myh3 (eMyHC), a marker of skeletal muscle regeneration. mRNA levels were normalized to cyclophilin and the subsequent ratios were presented as relative expression compared with WT values. fTibialis anterior sections stained with hematoxylin-erythrosin-safran. Scale bar = 100 μm. g The percentage of muscle fibers with central nuclei was counted. Results are means ± SD; n = 6 mice per group. **p < 0.01; ***p < 0.001 vs. WT; ##p < 0.01; ###p < 0.001 vs. mdx mice

Mentions: Since ApN has been found to induce myogenesis in C2C12 cells [26], we explored different key markers involved in the skeletal myogenic program [25]. The expression of MyoD and Myf5 proteins, that activate satellite cells to proliferate [25], was markedly reduced in tibialis anterior of mdx mice when compared to WT mice (-80 and −60 %, respectively). The decrease of these proliferation markers, which may be ascribed to the inflammatory context [27, 28], was partially restored in mdx-ApN mice (Fig. 4a, b). Two later markers (early differentiation phase), myogenin and Mrf4, were next studied. Mrf4 showed a pattern of expression similar to that of the proliferation markers, while myogenin was increased in mdx mice and further upregulated in mdx-ApN ones (Fig. 4c, d). The regeneration marker, the embryonic myosin heavy chain (Myh3) behaved similarly (Fig. 4e).Fig. 4


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)

Effects of adiponectin on markers of the myogenic program in mdx mice. The expression of MyoD (a) and Myf5 (b), two myogenic regulatory factors, was analyzed by Western blotting in tibialis anterior muscles from the three groups of mice. Levels of each marker were normalized to actin levels. mRNA levels of Mrf4 (c) and myogenin (d), two markers of muscle differentiation. e mRNA levels of Myh3 (eMyHC), a marker of skeletal muscle regeneration. mRNA levels were normalized to cyclophilin and the subsequent ratios were presented as relative expression compared with WT values. fTibialis anterior sections stained with hematoxylin-erythrosin-safran. Scale bar = 100 μm. g The percentage of muscle fibers with central nuclei was counted. Results are means ± SD; n = 6 mice per group. **p < 0.01; ***p < 0.001 vs. WT; ##p < 0.01; ###p < 0.001 vs. mdx mice
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Effects of adiponectin on markers of the myogenic program in mdx mice. The expression of MyoD (a) and Myf5 (b), two myogenic regulatory factors, was analyzed by Western blotting in tibialis anterior muscles from the three groups of mice. Levels of each marker were normalized to actin levels. mRNA levels of Mrf4 (c) and myogenin (d), two markers of muscle differentiation. e mRNA levels of Myh3 (eMyHC), a marker of skeletal muscle regeneration. mRNA levels were normalized to cyclophilin and the subsequent ratios were presented as relative expression compared with WT values. fTibialis anterior sections stained with hematoxylin-erythrosin-safran. Scale bar = 100 μm. g The percentage of muscle fibers with central nuclei was counted. Results are means ± SD; n = 6 mice per group. **p < 0.01; ***p < 0.001 vs. WT; ##p < 0.01; ###p < 0.001 vs. mdx mice
Mentions: Since ApN has been found to induce myogenesis in C2C12 cells [26], we explored different key markers involved in the skeletal myogenic program [25]. The expression of MyoD and Myf5 proteins, that activate satellite cells to proliferate [25], was markedly reduced in tibialis anterior of mdx mice when compared to WT mice (-80 and −60 %, respectively). The decrease of these proliferation markers, which may be ascribed to the inflammatory context [27, 28], was partially restored in mdx-ApN mice (Fig. 4a, b). Two later markers (early differentiation phase), myogenin and Mrf4, were next studied. Mrf4 showed a pattern of expression similar to that of the proliferation markers, while myogenin was increased in mdx mice and further upregulated in mdx-ApN ones (Fig. 4c, d). The regeneration marker, the embryonic myosin heavy chain (Myh3) behaved similarly (Fig. 4e).Fig. 4

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