Integration of microRNA changes in vivo identifies novel molecular features of muscle insulin resistance in type 2 diabetes

Abstract

BackgroundSkeletal muscle insulin resistance (IR) is considered a critical component of type II diabetes, yet to date IR has evaded characterization at the global gene expression level in humans. MicroRNAs (miRNAs) are considered fine-scale rheostats of protein-coding gene product abundance. The relative importance and mode of action of miRNAs in human complex diseases remains to be fully elucidated. We produce a global map of coding and non-coding RNAs in human muscle IR with the aim of identifying novel disease biomarkers.MethodsWe profiled >47,000 mRNA sequences and >500 human miRNAs using gene-chips and 118 subjects (n = 71 patients versus n = 47 controls). A tissue-specific gene-ranking system was developed to stratify thousands of miRNA target-genes, removing false positives, yielding a weighted inhibitor score, which integrated the net impact of both up- and down-regulated miRNAs. Both informatic and protein detection validation was used to verify the predictions of in vivo changes.ResultsThe muscle mRNA transcriptome is invariant with respect to insulin or glucose homeostasis. In contrast, a third of miRNAs detected in muscle were altered in disease (n = 62), many changing prior to the onset of clinical diabetes. The novel ranking metric identified six canonical pathways with proven links to metabolic disease while the control data demonstrated no enrichment. The Benjamini-Hochberg adjusted Gene Ontology profile of the highest ranked targets was metabolic (P < 7.4 × 10-8), post-translational modification (P < 9.7 × 10-5) and developmental (P < 1.3 × 10-6) processes. Protein profiling of six development-related genes validated the predictions. Brain-derived neurotrophic factor protein was detectable only in muscle satellite cells and was increased in diabetes patients compared with controls, consistent with the observation that global miRNA changes were opposite from those found during myogenic differentiation.ConclusionsWe provide evidence that IR in humans may be related to coordinated changes in multiple microRNAs, which act to target relevant signaling pathways. It would appear that miRNAs can produce marked changes in target protein abundance in vivo by working in a combinatorial manner. Thus, miRNA detection represents a new molecular biomarker strategy for insulin resistance, where micrograms of patient material is needed to monitor efficacy during drug or life-style interventions.

Smoking induces differential miRNA expression in human spermatozoa: A potential transgenerational epigenetic concern?

“…In agreement with previous studies, a biological change (fold change) of ≥30%, p < 0.05 after BH correction was considered significant. 52,53 Validated mRNA targets of the 28 significantly differentially expressed miRNAs were downloaded from the miRWalk database (latest update March 29, 2011). 42 In addition, mRNAs predicted by both the miRWalk and DIANA-microT algorithms to be targets of the 28 altered miRNAs were downloaded from the miRWalk database.…”

The effects of creatine supplementation on thermoregulation and physical (cognitive) performance: a review and future prospects

“…miRNA has also been shown to influence skeletal muscle protein synthesis in vivo in humans (Gallagher et al 2010). Several miRNA species regulate muscle differentiation, specifically miR-133a/b, miR-206 and miR-1 (Chen et al 2006;Rao et al 2006).…”

Altered microRNA expression in skeletal muscle results from high-fat diet-induced insulin resistance in mice

“…All these indicate that microRNAs are essential for the development and function of skeletal muscle Altered microRNA expression in skeletal muscle results from high-fat diet-induced insulin resistance in mice and are considered to be a novel therapeutic target. However, the expression and role of microRNAs in skeletal muscle insulin resistance is not yet well established, although several studies have suggested that microRNAs are involved in skeletal muscle insulin resistance in animal models or type 2 diabetes patients (13,(20)(21)(22)(23). Therefore, in our study we established a skeletal muscle insulin resistance mouse model (mice were fed a high-fat diet) and sought to determine the expression profiles of microRNAs by microRNA microarray and examine the biological processes and signaling pathways involved in skeletal muscle insulin resistance by Gene Ontology (GO) and pathway mapping tools.…”