Skeletal muscle secretome in Duchenne muscular dystrophy: a pivotal anti-inflammatory role of adiponectin

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.

Fractal dimension analysis reveals skeletal muscle disorganization in mdx mice

“…Moreover, a transcriptome analysis of Ullrich congenital muscular dystrophy fibroblasts revealed increased expression of genes related to extracellular matrix, and Ogn was one of the Top 10 up-regulated transcript [30]. Although few studies have already identified differentially expressed secretome components in DMD [31,32], our muscle transcriptome reanalysis pointed out to Ogn as an important factor in regulating ECM organization in DMD, due to its role in coordinating appropriated collagen production, organization, and remodeling.…”

Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together?

“…We and others have shown that circulating levels of ApN are greatly decreased in mdx mice (mouse model of DMD) [56,100], an observation confirmed in human patients [101]. Moreover, myotubes from DMD patients were unable to produce ApN for local protection [57], unlike non-dystrophic myotubes challenged by inflammation [36]. Thus, there could be a rationale to therapeutically correcting the low levels of ApN in dystrophic patients.…”

“…Mice with muscle-specific disruption of AdipoR1 also exhibited a local decrease in oxidative-stress-detoxifying enzymes [11]. Moreover, ApN disclosed strong anti-inflammatory properties in human myotubes when submitted to an inflammatory challenge [56,57]. ApN could also put a brake on local inflammation by functioning as a direct regulator of macrophage phenotype favoring the switch from a pro-inflammatory M1-like state to an anti-inflammatory M2-like state, as shown in vivo and in vitro [58].…”

“…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]. The AMPK pathway is known to inhibit inflammation and oxidative stress by repressing the activity of the transcription factor, nuclear factor kappa B (NF-κB), a key inducer of inflammatory responses [59].…”

Links Between Adiponectin and Dementia: From Risk Factors to Pathophysiology

“…For example, Chabry et al (2015) showed that APN could reduce neuroinflammation and depressive-like behaviors in mice by regulating microglia and macrophage phenotype and activation state. Lecompte et al (2017) found that APN retained its anti-inflammatory feature in dystrophic muscle by activating the AdipoR1-AMPK-SIRT1-PGC-1αpathway in mice. Besides, Jian et al (2019) demonstrated that APN suppressed inflammatory response of microglia to amyloid-β oligomer (AβO) and APN deficiency may aggravate microglia-mediated neuroinflammation in AD mice.…”