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Role of microRNAs from myogenic progenitors in adult skeletal muscle function and the implications for type 2 diabetes

English title Role of microRNAs from myogenic progenitors in adult skeletal muscle function and the implications for type 2 diabetes
Applicant Krützfeldt Jan
Number 128474
Funding scheme SNSF Professorships
Research institution Klinik für Endokrinologie, Diabetologie und Klinische Ernährung Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Endocrinology
Start/End 01.10.2010 - 30.09.2014
Approved amount 1'538'405.00
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Lay Summary (English)

Lead
Lay summary
Diabetes mellitus type 2 (T2D) is a disease that has become a worldwide epidemic. It is characterized by rising glucose levels because the body does not respond adequately to insulin anymore. Skeletal muscle is an important tissue for the development of T2D as it usually stores most of the glucose after we eat. Skeletal muscle is also efficient for the treatment of T2D when it is activated by exercise and physical activity. Our aim is to understand which signals direct a muscle cell to form a healthy muscle that fully responds to insulin. Significance of this work Previous studies on skeletal muscle in T2D have mostly focused on fully differentiated skeletal muscle, while we are investigating muscle cells before they form muscle fibers. This approach could help us to understand novel aspects of why T2D develops and might also give rise to new therapeutic strategies. The results of this project are not limited to T2D, but could be relevant to other muscle-related diseases as well. There have been little advances in clinical approaches to treat muscle injury or muscle wasting. The identification of cellular signals that suppress the normal direction from a muscle cell to a healthy muscle fiber would impact many research areas. Aging has also been associated with exhaustion of muscle cells over time and targeting adverse cell signals could permit to preserve autonomy and muscle strength in the elderly. Finally, the increased incidence of heart failure and chronic obstructive pulmonary disease places a high priority on public health. Numerous studies have linked abnormalities in skeletal muscle to early fatigue and exhaustion in these populations. Targeting cell signals that prevent muscle fiber formation could therefore also offer new strategies to decrease illness in these patients. Methods Adult skeletal muscle is continuously replaced by muscle cells that fuse to preexisting muscle fibers or build new ones. We are isolating these muscle cells from different animal models and also from patients with T2D. We then study in these muscle cells the levels of genes called microRNAs that have only been discovered about 10 years ago. MicroRNAs have already been shown to be important cell signals that control the levels of many proteins. Their role in muscle cells has not been analyzed in detail yet. After we have characterized which microRNAs are present in muscle cells and how they are regulated in T2D we will also investigate their function. Our most important approach to achieve this goal is to silence these microRNAs in animal models using pharmacological inhibitors, called antagomirs.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
MicroRNA-29a in Adult Muscle Stem Cells Controls Skeletal Muscle Regeneration During Injury and Exercise Downstream of Fibroblast Growth Factor-2
Galimov Artur, Merry Troy L, Luca Edlira, Rushing Elisabeth J, MIzbani Amir, Turcekova Katarina, Hartung Angelika, Croce Carlo M, Ristow Michael, Krützfeldt Jan (2016), MicroRNA-29a in Adult Muscle Stem Cells Controls Skeletal Muscle Regeneration During Injury and Exercise Downstream of Fibroblast Growth Factor-2, in Stem Cells, 34(3), 768-780.
Growth hormone replacement therapy regulates microRNA-29a and targets involved in insulin resistance
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 J Mol Med , 93(12), 1369-1379.
microRNA deep sequencing in two adult stem cell populations identifies miR-501 as novel regulator of myosin heavy chain during muscle regeneration
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.

Collaboration

Group / person Country
Types of collaboration
University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Leipzig Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events



Self-organised

Title Date Place
EMBO workshop “The reciprocal interactions of signaling pathways and non-coding RNA” 16.09.2012 Ascona, Switzerland

Awards

Title Year
Wissenschaftspreis der Walter und Gertrud Siegenthaler Stiftung 2012
Young Independent Investigator Prize SGED 2011

Associated projects

Number Title Start Funding scheme
152978 Role of microRNAs from myogenic progenitors in adult skeletal muscle function and the implications for type 2 diabetes 01.10.2014 SNSF Professorships
157745 High-throughput assays for molecular markers of cytotoxicity 01.12.2014 R'EQUIP

Abstract

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.
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