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Mizbani Amir, Luca Edlira, Rushing Elisabeth J, Krützfeldt Jan, microRNA deep sequencing in two adult stem cell populations identifies miR-501 as novel regulator of myosin heavy chain during muscle regeneration, in Development
Insulin resistance is a major factor in the pathogenesis of type 2 diabetes (T2D) and decreased oxidative capacity in skeletal muscle has been proposed to explain this defect. Insulin resistance becomes apparent even when myogenic progenitors from individuals with T2D are expanded into human myotubes ex vivo. Consequently, the identification of the primary mechanisms involved is of great relevance. I postulate that microRNAs are critical for adult skeletal muscle function and the development of insulin resistance. MicroRNAs are a novel gene family of regulatory RNAs that have a profound impact on myogenesis and myocyte growth of both skeletal and cardiac muscle. Their specific role in myogenic progenitors from adult skeletal muscle has not been elucidated yet. I propose to identify microRNAs that are enriched in myogenic progenitors by comparing microRNA expression profiles from adult skeletal muscle and pure progenitor populations. Subsequently, I will study the impact of these microRNAs on adult skeletal muscle function in vitro and in vivo. To achieve this goal, primary myoblast cell lines will be established from conditional knockout mice (Dgcr8flox/flox) where microRNA synthesis can be shut down after adenoviral delivery of Cre recombinase. This system can be used to study the function of individual miRNAs by reintroducing specific miRNAs and testing their ability to rescue loss-of-function phenotypes. In a novel in vivo system, I will silence microRNAs in myogenic progenitors in mice through intramuscular injection of antisense oligonucleotides termed antagomirs. The functional consequences will be studied during expansion of the targeted myogenic progenitors ex vivo. Antagomir-treated progenitors will also be directly transplanted into a mouse model of muscle degeneration (dmd,mdx) to test myofiber formation and oxidative phosphorylation capacity in vivo. My ultimate goal is to attenuate insulin resistance in animal models using transplantation of antagomir-treated progenitors. I hypothesize that microRNAs are critical for adult skeletal muscle function, and will therefore screen progenitor microRNAs for aberrant expression in different skeletal muscle regeneration/degeneration models. Special emphasis will be given to study the implications of microRNA regulatory pathways for insulin resistance in humans and microRNA expression will be analysed in myogenic progenitors isolated from patients with T2D. My studies will provide new insights into posttranscriptional control mechanisms in skeletal muscle and relate them to insulin resistance. The results might facilitate the development of novel therapeutic strategies to treat T2D.