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Increasing evidence suggests that inflammation plays a central role in driving joint pathology in certain patients with osteoarthritis (OA). Since many patients with OA are obese and increased adiposity is associated with chronic inflammation, we investigated whether obese patients with hip OA exhibited differential pro-inflammatory cytokine signalling and peripheral and local lymphocyte populations, compared to normal weight hip OA patients. No differences in either peripheral blood or local lymphocyte populations were found between obese and normal-weight hip OA patients. However, synovial fibroblasts from obese OA patients were found to secrete greater amounts of the pro-inflammatory cytokine IL-6, compared to those from normal-weight patients (p < 0.05), which reflected the greater levels of IL-6 detected in the synovial fluid of the obese OA patients. Investigation into the inflammatory mechanism demonstrated that IL-6 secretion from synovial fibroblasts was induced by chondrocyte-derived IL-6. Furthermore, this IL-6 inflammatory response, mediated by chondrocyte-synovial fibroblast cross-talk, was enhanced by the obesity-related adipokine leptin. This study suggests that obesity enhances the cross-talk between chondrocytes and synovial fibroblasts via raised levels of the pro-inflammatory adipokine leptin, leading to greater production of IL-6 in OA patients.

By interacting with proteins and nucleic acids, the vast family of mammalian circRNAs is proposed to influence many biological processes. Here, RNA sequencing analysis of circRNAs differentially expressed during myogenesis revealed that circSamd4 expression increased robustly in mouse C2C12 myoblasts differentiating into myotubes. Moreover, silencing circSamd4, which is conserved between human and mouse, delayed myogenesis and lowered the expression of myogenic markers in cultured myoblasts from both species. Affinity pulldown followed by mass spectrometry revealed that circSamd4 associated with PURA and PURB, two repressors of myogenesis that inhibit transcription of the myosin heavy chain (MHC) protein family. Supporting the hypothesis that circSamd4 might complex with PUR proteins and thereby prevent their interaction with DNA, silencing circSamd4 enhanced the association of PUR proteins with the Mhc promoter, while overexpressing circSamd4 interfered with the binding of PUR proteins to the Mhc promoter. These effects were abrogated when using a mutant circSamd4 lacking the PUR binding site. Our results indicate that the association of PUR proteins with circSamd4 enhances myogenesis by contributing to the derepression of MHC transcription.

BackgroundThere 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 bodyThe 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.ConclusionUnderstanding 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.