Rolle der mikroRNA für die hormonabhängige Regeneration und Funktion des Skelettmuskels

Der Skelettmuskel ist das grösste Organ des Menschen und für die Gesundheit von zentraler Bedeutung. Dies zeigt sich an den positiven Wirkungen von körperlicher Aktivität, aber auch an vielen Erkrankungen, bei denen die Regeneration und/oder Funktion des Muskels eingeschränkt sind. Hierzu zählen zum Beispiel der Diabetes mellitus Typ 2, bei dem der Skelettmuskel nicht mehr ausreichend auf Insulin anspricht, die altersabhängige Abnahme der Muskelmasse sowie Veränderungen der Muskulatur während der Ersatztherapie mit Hormonen wie Wachstums- oder Schilddrüsenhormon. Unsere Arbeitsgruppe untersucht, welche Rolle mikroRNAs bei diesen Veränderungen spielen. mikroRNAs sind kleine RNA Moleküle, die erst vor wenigen Jahren entdeckt wurden. Sie sind an der Regulation der Proteinbildung in der Zelle beteiligt, indem sie sich an andere RNA Moleküle anbinden und ihre Umschreibung in Protein reduzieren. Unser Ziel ist es durch ein besseres Verständnis der molekularen Grundlagen von muskelabhängigen Erkrankungen und ihren Komplikationen eine frühzeitige Erkennung zu ermöglichen sowie neue therapeutische Ansätze aufzuzeigen.

Aktuelle Projekte

  • SNF Grant PP00P3_152978 „Role of microRNAs from myogenic progenitors in adult skeletal muscle function and the implications for type 2 diabetes“
  • SNF Grant PDFMP3_141761 „Mechanisms of ectopic brown adipose tissue formation in normal and insulin resistant states“
  • Clinical Research Focus Program of the University of Zurich “Small RNAs”
  • Member of the Systems X project “HDLX”

Introduction

 

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Skeletal muscle is a key target tissue for therapeutic interventions in obesity, type 2 diabetes as well as for cardiovascular health in general. Skeletal muscle is fundamental to whole-body metabolism as 30-70% of postprandial glucose is utilized by this tissue. Skeletal muscle is also essential for lipid metabolism as it covers 80-90% of its energy requirements in the resting state through the uptake and oxidation of fatty acids. We are especially interested in utilizing the potential of adult muscle stem cells, termed satellite cells or myogenic progenitors, to improve insulin responsiveness of muscle tissue and glucose homeostasis.

Adult skeletal muscle function relies on maintenance and regeneration of functional myofibers throughout life. Myogenic progenitors are responsible for this remarkable plasticity with 1-2% of myonuclei being replaced weekly. In fact, following postnatal growth, the majority of adult myonuclei are derived from myogenic progenitors. These cells are located under the basal lamina of each muscle fiber. They are part of the adult muscle stem cell compartment (AMSC) together with different progenitor populations. The molecular basis for the heterogeneity of the AMSC is poorly understood, but it is critical for the regeneration of skeletal muscle and could contribute to either the development of muscle fiber subtypes or the formation of different mesenchymal cell lineages.

I.  Posttranscriptional control mechanisms in skeletal muscle



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MicroRNAs are regulators of gene expression at the posttranscriptional level that play important roles in many if not all biological processes. During myogenesis several microRNAs have been linked to the regulation of important developmental pathways. Our group is interested to identify microRNAs that can be targeted for the generation of metabolically active myofibers and thus improvement of glucose homeostasis. To achieve this aim, we are isolating myogenic progenitors and other cell lineages from adult skeletal muscle of animals and humans. We are profiling microRNA expression in different metabolic states and use loss-of-function and gain-of-function approaches to study the impact of candidate microRNAs on muscle regeneration, fiber type differentiation, oxidative phosphorylation capacity and insulin responsiveness. In addition to genetic approaches, our group is especially interested in silencing microRNAs using oligonucleotides such as antagomirs that have promising clinical applications.

As part of the Clinical Research Focus Program of the University of Zurich (KFSP) “Small RNAs” we apply high-throughput approaches to screen for microRNAs that regulate the metabolic function of human skeletal muscle and investigate the underlying pathways.
With our studies we hope to gain new insights into posttranscriptional control mechanisms in skeletal muscle and their role in insulin resistance and type 2 diabetes.

II. Ectopic fat formation in adult skeletal muscle

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Recent evidence points to an unexpected role of adipose tissue at ectopic locations such as adult skeletal muscle, where white adipose tissue is a critical regulator of muscle regeneration, while brown adipose tissue between muscle bundles protects against obesity.

It is still unknown which progenitor populations of adult skeletal muscle give rise to different adipose lineages and how they contribute to the development of insulin resistance. We study the formation of fat tissue in adult skeletal muscle tissue and apply sorting protocols for prospective isolation of distinct progenitor populations. Furthermore, we are generating animal models that allow for tracing of the myogenic lineage in vivo. Our approach also includes the use of genetic ablation of specific progenitor populations under normal and insulin resistant conditions. We expect our experiments to clarify the contribution of different adult progenitor populations to ectopic fat formation and the development of insulin resistance. This knowledge could help to understand mechanisms how adult skeletal muscle regulates whole body metabolism and might lead to novel protocols to increase energy expenditure and treat obesity.

Auskunft

PD Dr. med. Jan Krützfeldt
Tel. +41 44 255 36 20
Fax +41 44 255 97 41
jan.kruetzfeldt@usz.ch

Team

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PD Dr. med. Jan Krützfeldt, Oberarzt
Sebastian Mathes,
PhD Doktorand
Tatiane Gorski, MSc,
PhD Doktorandin
​Edlira Luca , PhD,
Wissenschaftliche Mitarbeiterin
 

 

 

Alumni

Wissenschaftliche Mitarbeitende
Dr. rer. nat. Angelika Hartung

PhD Studenten
Artur Galimov
Amir Mizbani
Katarina Turcekova 

Kontaktadresse

UniversitätsSpital Zürich
Klinik für Endokrinologie, Diabetologie
und Klinische Ernährung
PD Dr. med. Jan Krützfeldt
Rämistrasse 100
8091 Zürich

Publikationen, Auswahl

microRNA deep sequencing in two adult stem cell populations identifies miR-501 as novel regulator of myosin heavy chain during muscle regeneration
Amir Mizbani, Edlira Luca, Elisabeth J. Rushing, and Jan Krützfeldt
Development. 2016 Nov 15;143(22):4137-4148.

Strategies to use microRNAs as therapeutic targets
Jan Krützfeldt
Best Pract Res Clin Endocrinol Metab. 2016 Oct;30(5):551-561. doi: 10.1016/j.beem.2016.07.004.

microRNA-29a in adult muscle stem cells controls skeletal muscle regeneration during injury and exercise downstream of fibroblast growth factor-2
Galimov A, Merry TL, Luca E, Rushing EJ, Mizbani A, Turcekova K, Hartung A, Croce CM, Ristow M, and Krützfeldt J
Stem Cells. 2016 Jan 5. doi: 10.1002/stem.2281. [Epub ahead of print]

Growth hormone replacement therapy regulates microRNA-29a and targets involved in insulin resistance
Galimov A1, Hartung A, Trepp R, Mader A, Flück M, Linke A, Blüher M, Christ E, Krützfeldt J.
J Mol Med (Berl). 2015 Dec;93(12):1369-79. doi: 10.1007/s00109-015-1322-y.

MicroRNA-194 is a target of transcription factor 1 (Tcf1, Hnf1 α in adult liver and controls expression of frizzled-6
Krützfeldt J, Rösch N, Hausser J, Manoharan M, Zavolan M, Stoffel M.
Hepatology. 2012 Jan;55(1):98-107

Specificity, duplex degradation and subcellular localization of antagomirs
Krützfeldt J, Kuwajima S, Braich R, Rajeev KG, Pena J, Tuschl T, Manoharan M, Stoffel M.
Nucleic Acids Res. 2007 April; 35(9):2885-92

MicroRNAs: A new class of regulatory genes affecting metabolism
Krützfeldt J, Stoffel M.
Cell Metab. 2006 Jul;4(1):9-12

Silencing of microRNAs in vivo with 'antagomirs'
Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M.
Nature. 2005 Dec 1;438(7068):685-9

Strategies to determine the biological function of microRNAs
Krützfeldt J, Poy MN, Stoffel M.
Nat Genet. 2006 Jun;38 Suppl 1:S14-9