Involvement of adiponectin in the pathogenesis of dystrophinopathy
Open accessAbstract
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.
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ApN disclosed strong anti-inflammatory properties in human myotubes when submitted to an inflammatory challenge.
“Moreover, ApN disclosed strong anti-inflammatory properties in human myotubes when submitted to an inflammatory challenge [56,57].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
The anti-inflammatory effects of ApN in human healthy myotubes were linked to activation of the AdipoR1-AMPK-SIRT1-PGC-1α pathway.
“Mechanistically, the anti-inflammatory effects of ApN in human “healthy” myotubes were linked to activation of the AdipoR1-AMPK-SIRT1-PGC-1α pathway [56,57].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
ApN activates the expression of two key factors of muscle differentiation, Myogenin and Mrf4, which are essential for provoking cell fusion into multinucleated myotubes.
“Third, ApN can coordinate the last step of skeletal muscle regeneration. Indeed, it activates the expression of two key factors of muscle differentiation, Myogenin and Mrf4 [56], which are essential for provoking cell fusion into multinucleated myotubes [67] (Figure 3).”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
Up-regulation of Myf5 by ApN in skeletal muscle allows the activation of satellite cells and their commitment to regenerate the skeletal muscle.
“First, up-regulation of Myf5 by ApN in skeletal muscle [56] allows the activation of satellite cells and their commitment to regenerate the skeletal muscle [67].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
gApN induces the expression of MyoD that allows myoblast proliferation and differentiation.
“Second, gApN induces the expression of MyoD that allows myoblast proliferation and differentiation [56,69,70].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
Skeletal muscles of mdx-ApN mice displayed higher expression of two major factors of muscle proliferation (Myf5 and MyoD), and two major factors of muscle differentiation (Myogenin and Mrf4).
“Skeletal muscles of mdx-ApN mice displayed higher expression of two major factors of muscle proliferation (Myf5 and MyoD), and two major factors of muscle differentiation (Myogenin and Mrf4) [56,67].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
ApN can act as preventive agent and delay disease progression in mdx mice overexpressing ApN.
“Indeed, when we generated transgenic mdx mice overexpressing ApN (mdx-ApN mice), we showed that ApN can act as preventive agent and delay disease progression [56].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
Replenishment of ApN by transgenesis or gene electro-transfer mitigated the dystrophic phenotype in mdx mice.
“Replenishment of ApN by transgenesis or gene electro-transfer mitigated the dystrophic phenotype in mdx mice [56,102].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
M1 macrophages actually switched into M2 (tissue-healing) state.
“M1 macrophages actually switched into M2 (tissue-healing) state.”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
mdx-ApN mice exhibited a more oxidative and resistant myofiber (type 1) phenotype.
“Third, mdx-ApN mice exhibited a more oxidative and resistant myofiber (type 1) phenotype.”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
ApN also up-regulated utrophin, an analogue of dystrophin, which partly compensated the lack of this scaffolding protein.
“Fourth, ApN also up-regulated utrophin, an analogue of dystrophin, which partly compensated the lack of this scaffolding protein.”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
Reduction of plasma creatine kinase and lactate dehydrogenase and curtailed extravasation of i.p. dye solution into muscles mirrored the strengthening of sarcolemmal integrity.
“Reduction of plasma creatine kinase and lactate dehydrogenase and curtailed extravasation of i.p. dye solution into muscles mirrored the strengthening of sarcolemmal integrity [56].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
The mechanisms leading to protective effects of ApN/AdipoRon in DMD involved activation of the AdipoR1-AMPK-SIRT1-PGC-1α axis both in vivo (mdx mice) and in vitro (human dystrophic myotubes).
“As in healthy muscle, the mechanisms leading to the protective effects of ApN/AdipoRon in DMD involved the activation of the AdipoR1-AMPK-SIRT1-PGC-1α axis both in vivo (mdx mice) or in vitro (human dystrophic myotubes) [56,57,103]”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
Silencing each component of the AdipoR1-AMPK-SIRT1-PGC-1α cascade abrogated the effects of ApN/AdipoRon.
“Silencing each component of this cascade abrogated the effects of ApN/AdipoRon.”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
ApN/AdipoRon supplementation retained its anti-inflammatory properties in DMD human myotubes.
“We found that ApN/AdipoRon supplementation retained its anti-inflammatory properties in DMD human myotubes [56,57,103]”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
ApN/AdipoRon supplementation induced a shift in the secretion of downstream myokines toward a less inflammatory profile in DMD human myotubes.
“and induced a shift in the secretion of downstream myokines toward a less inflammatory profile.”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
Enhanced mitochondrial biogenesis and oxidative metabolism will induce a switch towards an oxidative and more resistant fiber phenotype.
“Second, enhanced mitochondrial biogenesis and oxidative metabolism will induce a switch towards an oxidative and more resistant fiber phenotype [56,102].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
The anti-inflammatory action of ApN/AdipoRon in DMD is ascribed to NF-κB inhibition by PGC-1α dephosphorylation and SIRT1 deacetylation.
“The anti-inflammatory action of ApN/AdipoRon in DMD is crucial and has been ascribed to NF-κB inhibition by PGC-1α dephosphorylation, SIRT1 deacetylation [56]”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
Up-regulation of utrophin partly substitutes for dystrophin deficiency.
“Third, up-regulation of utrophin partly substitutes for dystrophin deficiency [56,57].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [56]
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References 49 · Cited by 55
- Authors
- Abou-Samra, M., Lecompte, S., Schakman, O., Noel, L., Many, M. C., Gailly, P., & Brichard, S. M.
- Affiliations
- UCLouvain (BE)
- Corresponding author
- Brichard, Sonia M.
- Venue
- Skeletal Muscle
- Published
- 2015-08-07
- Volume
- 5
- Issue
- 1
- Pages
- 25-25
- ISSN
- 2044-5040 (ISSN-L)
- PMC
- PMC4528853
- OpenAlex
- W2098115999
- Cited by
- 55
- References
- 49
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 6 · 2021: 10 · 2020: 7 · 2019: 6 · 2018: 3 · 2017: 6 · 2016: 2
- FWCI
- 1.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Skeletal Muscle (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Libraries (submittedVersion, other-oa)
- Funders
- Association Française contre les Myopathies
- French Muscular Dystrophy Association
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Keywords
- adiponectin, Duchenne muscular dystrophy, dystrophinopathy, mdx mice, muscle inflammation, oxidative stress, utrophin, AdipoR1, AMPK/SIRT1/PGC-1α signaling, NF-κB, muscle regeneration, skeletal muscle injury, myotubes, therapeutic target
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