Project

Back to overview

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 152978
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 01.10.2014 - 30.09.2015
Approved amount 405'772.00
Show all

Keywords (9)

skeletal muscle; microRNAs; glucose metabolism; myogenesis; myogenic progenitors; insulin resistance; glycolysis; mitochondrial activity; type 2 diabetes

Lay Summary (German)

Lead
Kleine RNA Moleküle, genannt mikroRNAs, enthalten keine Information für die Herstellung von Eiweissen, sondern haben sich auf die Steuerung anderer RNA Moleküle spezialisiert. Hierdurch üben sie eine wichtige Funktion in den Körperzellen des Menschen aus. Die genaue Rolle der mikroRNAs bei der Regulation von Skelettmuskel-Entstehung und seiner Funktion beim Menschen sind bislang unzureichend verstanden. Das Projekt leistet hierzu einen Beitrag.
Lay summary

Eine gestörte Funktion der Skelettmuskulatur spielt eine wichtige Rolle bei der Entwicklung von Typ-2-Diabetes mellitus. Hierzu zählt die sogenannte Insulinresistenz also das verminderte Ansprechen der Muskulatur auf das Hormon Insulin. Patienten mit Diabetes mellitus leiden häufig auch an Mängel bei der Ausbildung und Reparatur von Skelettmuskel, zum Beispiel bei der Herstellung von unterschiedlichen Muskelfasertypen. Die zugrunde liegenden molekularen Mechanismen sind noch unzureichend verstanden. Wir untersuchen die Rolle von mikroRNAs in der Skelettmuskulatur von Tiermodellen und beim Menschen. Unser Ziel ist es, mikroRNAs und deren Zielgene, die in insulinresistentem Muskel reguliert werden, zu identifizieren und hinsichtlich ihrer therapeutischen Anwendbarkeit zu überprüfen. Um dieses Ziel zu erreichen, haben wir in den letzten 3 Jahren verschiedene Modelle entwickelt und erste mikroRNA Kandidaten identifiziert. In der nächsten Phase werden wir diese mikroRNAs systematisch untersuchen, indem wir sie in Tiermodellen durch genetische und pharmakologische Methoden ausschalten und so ihre Funktion testen. Um die Rolle dieser mikroRNAs beim Menschen zu überprüfen, werden wir in einer zweiten Phase die Menge dieser mikroRNAs im Skelettmuskel des Menschen unter unterschiedlichen Bedingungen messen, zum Beispiel nach Sport oder nach dem Einsetzen von Insulinresistenz. Unsere Untersuchungen werden dazu beitragen, die Rolle der mikroRNAs bei der Skelettmuskel-Funktion besser zu verstehen. 

Das Projekt befasst sich mit Grundlagenforschung, die einen translationalen Ansatz hat, also auf die direkte Anwendbarkeit beim Menschen hinzielt. Unser Ziel ist es neue therapeutische Ansätze zu identifizieren, die bei verschiedenen Krankheiten beim Menschen, bei denen der Skelettmuskel eine wichtige Rolle spielt, einsetzbar sein könnten. Dazu gehört die Entstehung des Diabetes mellitus, aber auch andere Erkrankungen wie zum Beispiel die altersabhängige Abnahme der Muskelmasse.

Direct link to Lay Summary Last update: 18.09.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Genetic deletion of microRNA biogenesis in muscle cells reveals a hierarchical non-clustered network that controls focal adhesion signaling during muscle regeneration
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, 36, 100967-100967.
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 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, 143(22), 4137-4148.
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 Journal of Molecular Medicine, 93(12), 1369-1379.
microRNA-29a in adult muscle stem cells controls skeletal muscle regeneration during injury and exercise downstream of fibroblast growth factor-2
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.

Collaboration

Group / person Country
Types of collaboration
Prof. Michael Ristow, ETH Zürich Switzerland (Europe)
- Publication
Prof. Christ, Inselspital Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Rushing, University of Zurich Switzerland (Europe)
- Publication
Prof. Matthias Blüher, Medical Department III, University of Leipzig Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Carlo Croce, The Ohio State University United States of America (North America)
- Publication

Associated projects

Number Title Start Funding scheme
128474 Role of microRNAs from myogenic progenitors in adult skeletal muscle function and the implications for type 2 diabetes 01.10.2010 SNSF Professorships
157745 High-throughput assays for molecular markers of cytotoxicity 01.12.2014 R'EQUIP

Abstract

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.
-