Abstract
BackgroundPersistent inflammation exacerbates the progression of Duchenne muscular dystrophy (DMD). The hormone, adiponectin (ApN), which is decreased in the metabolic syndrome, exhibits anti-inflammatory properties on skeletal muscle and alleviates the dystrophic phenotype of mdx mice. Here, we investigate whether ApN retains its anti-inflammatory action in myotubes obtained from DMD patients. We unravel the underlying mechanisms by studying the secretome and the early events of ApN.MethodsPrimary cultures of myotubes from DMD and control patients were treated or not by ApN after an inflammatory challenge. Myokines secreted in medium were identified by cytokine antibody-arrays and ELISAs. The early events of ApN signaling were assessed by abrogating selected genes.ResultsApN retained its anti-inflammatory properties in both dystrophic and control myotubes. Profiling of secretory products revealed that ApN downregulated the secretion of two pro-inflammatory factors (TNFα and IL-17A), one soluble receptor (sTNFRII), and one chemokine (CCL28) in DMD myotubes, while upregulating IL-6 that exerts some anti-inflammatory effects. These changes were explained by pretranslational mechanisms. Earlier events of the ApN cascade involved AdipoR1, the main receptor for muscle, and the AMPK-SIRT1-PGC-1α axis leading, besides alteration of the myokine profile, to the upregulation of utrophin A (a dystrophin analog).ConclusionApN retains its beneficial properties in dystrophic muscles by activating the AdipoR1-AMPK-SIRT1-PGC-1α pathway, thereby inducing a shift in the secretion of downstream myokines toward a less inflammatory profile while upregulating utrophin. ApN, the early events of the cascade and downstream myokines may be therapeutic targets for the management of DMD.
Highlights
Duchenne muscular dystrophy (DMD) is an X-linked muscle disease, with a prevalence of 1 in 3500 boys worldwide
ApN mRNA and secretion from dystrophic myotubes were decreased by ~60% and ~15%, respectively (Fig. 2a, b). This suggests a potential deficiency of ApN in DMD myotubes and supports the rationale behind recommending ApN supplementation in muscle dystrophy
Mechanisms underlying the beneficial effects of adiponectin in control and DMD myotubes We investigated whether the signaling pathway linking Adiponectin receptor 1 (AdipoR1)-SIRT1-PGC-1α was involved in the anti-inflammatory action of ApN in DMD myotubes, as previously shown in healthy myotubes [18]
Summary
Duchenne muscular dystrophy (DMD) is an X-linked muscle disease, with a prevalence of 1 in 3500 boys worldwide. Contraction of dystrophin-deficient myofibers produces severe damage and generates cycles of muscle fiber necrosis and regeneration [2] These alterations lead to chronic inflammation, which is a crucial feature of the pathogenesis of this disease [3]. Profiling of secretory products revealed that ApN downregulated the secretion of two pro-inflammatory factors (TNFα and IL17A), one soluble receptor (sTNFRII), and one chemokine (CCL28) in DMD myotubes, while upregulating IL-6 that exerts some anti-inflammatory effects. These changes were explained by pretranslational mechanisms.
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