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New targets to alleviate skeletal muscle inflammation: role of microRNAs regulated by adiponectin.

ABSTRACT: Muscle inflammation worsens metabolic disorders as well as devastating myopathies. The hormone adiponectin (ApN) has emerged has a master regulator of inflammation/immunity in several tissues including the skeletal muscle. In this work, we explore whether microRNAs regulated by ApN may represent novel mechanisms for controlling muscle inflammation. By screening arrays, we found miR-711 as a strong candidate for mediating ApN action. Thus, ApN-knockout mice showed decreased muscular expression of miR-711 together with enhanced inflammation/oxidative stress markers, while mice overexpressing ApN showed increased miR-711 levels. Likewise, electrotransfer of the ApN gene in muscle of ApN-knockout mice upregulated miR-711 while reducing inflammation and oxidative stress. Similar data were obtained in murine C2C12 cells or in human primary myotubes treated with ApN. MiR-711 overexpression downregulated several components of the Toll-like receptor-4 (TLR4) pathway, which led to repression of NF-?B activity and downstream pro-inflammatory cytokines. MiR-711 blockade had opposite effects. Moreover, muscle electrotransfer of pre-miR-711 recapitulated in vivo the anti-inflammatory effects observed in vitro. Thus, miR-711, which is upregulated by ApN represses TLR4 signaling, acting therefore as a major mediator of the anti-inflammatory action of ApN. This novel miRNA and its related target genes may open new therapeutic perspectives for controlling muscle inflammation.

SUBMITTER: Boursereau R

PROVIDER: S-EPMC5327483 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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New targets to alleviate skeletal muscle inflammation: role of microRNAs regulated by adiponectin.

Boursereau Raphaël R Abou-Samra Michel M Lecompte Sophie S Noel Laurence L Brichard Sonia M SM

Scientific reports 20170227

Muscle inflammation worsens metabolic disorders as well as devastating myopathies. The hormone adiponectin (ApN) has emerged has a master regulator of inflammation/immunity in several tissues including the skeletal muscle. In this work, we explore whether microRNAs regulated by ApN may represent novel mechanisms for controlling muscle inflammation. By screening arrays, we found miR-711 as a strong candidate for mediating ApN action. Thus, ApN-knockout mice showed decreased muscular expression of ...[more]

PMID: 28240307

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Project description:Background:There is currently an unmet clinical need to develop better pharmacological treatments to improve glucose handling in Type II Diabetes patients with obesity. To this end, determining the effect of obesity-associated adipokines on skeletal muscle insulin sensitivity has emerged as an important area of drug discovery research. This review draws together the data on the functional role of adipokines on skeletal muscle insulin signalling, highlights several understudied novel adipokines and provides a perspective on the direction of future research. Main body:The adipokines leptin, resistin, visfatin and adiponectin have all been shown to affect skeletal muscle insulin sensitivity by impacting on the activity of components within insulin signalling pathways, affecting GLUT4 translocation and modulating insulin-mediated skeletal muscle glucose uptake. Furthermore, proteomic analysis of the adipose tissue secretome has recently identified several novel adipokines including vaspin, chemerin and pref-1 that are associated with obesity and insulin resistance in humans and functionally impact on insulin signalling pathways. However, predominantly, these functional findings are the result of studies in rodents, with in vitro studies utilising either rat L6 or murine C2C12 myoblasts and/or myotubes. Despite the methodology to isolate and culture human myoblasts and to differentiate them into myotubes being established, the use of human muscle in vitro models for the functional validation of adipokines on skeletal muscle insulin sensitivity is limited. Conclusion:Understanding the mechanism of action and function of adipokines in mediating insulin sensitivity in skeletal muscle may lead to the development of novel therapeutics for patients with type 2 diabetes. However, to date, studies conducted in human skeletal muscle cells and tissues are limited. Such human in vitro studies should be prioritised in order to reduce the risk of candidate drugs failing in the clinic due to the assumption that rodent skeletal muscle target validation studies will to translate to human.

Dataset Information

New targets to alleviate skeletal muscle inflammation: role of microRNAs regulated by adiponectin.

Publications

New targets to alleviate skeletal muscle inflammation: role of microRNAs regulated by adiponectin.

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