skeletal muscle; microRNAs; glucose metabolism; myogenesis; myogenic progenitors; insulin resistance; glycolysis; mitochondrial activity; type 2 diabetes
Luca Edlira, Turcekova Katarina, Hartung Angelika, Mathes Sebastian, Rehrauer Hubert, Krützfeldt Jan (2020), Genetic deletion of microRNA biogenesis in muscle cells reveals a hierarchical non-clustered network that controls focal adhesion signaling during muscle regeneration, in Molecular Metabolism
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Mizbani Amir, Luca Edlira, Rushing Elizabeth Jane, Krützfeldt Jan (2016), microRNA deep sequencing in two adult stem cell populations identifies miR-501 as novel regulator of myosin heavy chain during muscle regeneration, in Development
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Galimov Artur, Hartung Angelika, Trepp Roman, Mader Alexander, Flück Martin, Linke Axel, Blüher Matthias, Christ Emanuel, Krützfeldt Jan (2015), Growth hormone replacement therapy regulates microRNA-29a and targets involved in insulin resistance, in Journal of Molecular Medicine
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Galimov Artur, microRNA-29a in adult muscle stem cells controls skeletal muscle regeneration during injury and exercise downstream of fibroblast growth factor-2, in Stem Cells
Insulin resistance of skeletal muscle plays a major role in the development of type 2 diabetes (T2D). Skeletal muscle from patients with T2D is characterized by decreased insulin-stimulated glucose uptake and changes in intracellular glucose metabolism which contribute to hyperglycemia. Patients with T2D also suffer from defects in myogenesis. The underlying molecular mechanisms which affect muscle regeneration are less well understood than the defects in glucose metabolism. However, decreased capacity to maintain muscle mass and diminished adaptive responses to exercise could contribute to the development of T2D. Thus, research aimed at improving muscle growth and muscle regenerative capacity might identify novel therapeutic strategies to treat the disease. We are investigating the role of microRNAs (miRNAs) in adult myogenesis and their interaction with skeletal muscle glucose metabolism. Our aim is to identify miRNAs and their target genes that are regulated in insulin resistant muscle and that can be therapeutically targeted to improve muscle fiber formation and growth in T2D patients. To achieve this goal we have established over the last 3 years various in vitro and in vivo systems. By maintaining myogenic progenitors ex vivo as well as by investigating miRNA expresion in adult skeletal muscle from both animals and humans, we have identified miR-29 as an important player in the muscle regeneration process and for glucose metabolism in adult skeletal muscle. To identify novel miRNAs involved in muscle regeneration in vivo we analysed the small RNA profile in myogenic progenitor cells after the onset of muscle injury using Ilumina deep sequencing. We show that activation of myogenic progenitors induces a highly expressed and tissue-specific miRNA with yet unknown function, termed pre-myomir-1. Finally, to identify novel miRNA interactions and miRNA targets that are relevant for myogenesis, we have developed a cell-based assay in which we can genetically deplete myoblasts from miRNA expression (Dgcr8flox/flox x Pax7CreER/+). Induction of Cre recombinase deletes the RNA binding protein Dgcr8 and leads to a gradual decrease of miRNA expression with a t1/2 of ~2 days. Using a miRNA library screen based on miRNA abundance in myoblasts we identified a subset of miRNAs that was able to rescue the differentiation defects of Dgcr8-depleted muscle cells. Reducing the miRNA expression in myoblasts to only a small subset will greatly facilitate the identification of miRNA targets that control myogenesis and provide insights into cooperative actions of miRNAs during muscle differentiation. Our results could be relevant for the design of therapeutic strategies not only in T2D, but also in other muscle-related diseases where myogenesis is affected, such as muscle dystrophy or ageing-associated sarcopenia. Finally, prediction of insulin resistance and exercise responses in humans by skeletal muscle miRNAs offers the opportunity to individually design prevention programs in patients at risk to develop T2D.