Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Skeletal Muscle Atrophy in Heart Failure – MDC and Charité Researchers Elucidate Mechanism

12.08.2015

It is a paradox: Patients with advanced congestive heart failure lose skeletal muscle mass, but their heart muscles become enlarged to provide the body with an adequate supply of blood and thus with oxygen. It has long been known that the protein angiotensin II plays a villainous role in this process. Now Dr. Philipp Du Bois and the cardiologist PD Dr. Jens Fielitz of the Experimental and Clinical Research Center (ECRC) of the Max Delbrück Center (MDC) and the Charité – Universitätsmedizin Berlin, and Professor Eric N. Olson (University of Texas Southwestern Medical Center, Dallas, Texas, USA) have elucidated the process and identified new therapeutic targets (Circulation Research)*.

Congestive heart failure is one of the leading causes of death in industrialized countries. The disease has various causes, including high blood pressure, coronary artery disease, diabetes, obesity and age. “Thanks to improved medical care, we can now provide effective treatment for patients with heart failure and can improve their prognosis, i.e. extend their survival time.

However, this also means that we increasingly have patients in the advanced stage of the disease. They lose a lot of weight, which worsens their condition and becomes life threatening. This is mainly caused by the wasting of skeletal muscles, also called skeletal muscle atrophy, which leads to decreased muscle strength. Unfortunately, we are not able to successfully treat this concomitant disease,” said Dr. Fielitz. The cardiologist from the Virchow Clinic of the Charité heads the independent research group “Protein Regulation in Heart and Skeletal Muscle” at the ECRC in Berlin-Buch.

Angiotensin II induces muscle atrophy
From previous studies, it was known that the activation of the renin-angiotensin system (RAAS) in patients with heart failure leads to the wasting of skeletal muscles. This intricate system of hormones and enzymes normally regulates the water and salt balance of the body as well as blood pressure. Patients with heart failure have elevated levels of one of the players of this system in the blood, angiotensin II.

It was also known that angiotensin II was the villain that induced muscle atrophy. Angiotensin II activates the ubiquitin proteasome system (UPS), the body’s cellular shredding machine, to degrade proteins by forming a muscle enzyme to act as a switch. As soon as the muscle enzyme MuRF1 is activated, the UPS machinery degrades muscle proteins in the patients, causing the muscles to become thinner and weaker.

If the patients are administered an ACE inhibitor, the wasting of the skeletal muscles is reduced. ACE inhibitors block the formation of angiotensin II and are conventionally used in the treatment of heart failure patients. “Although ACE inhibitors are effective, they cannot completely halt the muscle wasting process. Often, after five to ten years, the treatment fails fails,” said Dr. Fielitz, explaining the problem.

New regulator and signaling pathway discovered
Moreover, the exact signaling pathway through which angiotensin II increases the formation of MuRF1 was hitherto not completely understood. But a full understanding is essential for finding new approaches to improved therapy. Dr. Fielitz and his colleagues therefore sought to find out exactly how angiotensin II increases the formation of MuRF1 in muscle cells and which signaling pathway regulates this muscle enzyme.

For this purpose, they performed a cDNA expression screen of a human skeletal muscle cDNA library comprising 250,000 individual cDNA expression plasmids, hoping to find new transcription factors amenable to regulate MuRF1 in muscle. And they found what they were looking for – the transcription factor EB (TFEB). It binds to special regulators in the MuRF1 gene and thereby induces the production of this muscle enzyme. The researchers showed that TFEB increases the expression of MuRF1 in muscle cells seventyfold. TFEB is thus the strongest activator of MuRF1 expression known up to now and a key constituent of muscle atrophy.

But there are other key elements in this complex regulation pathway which is ultimately triggered by angiotensin II. The activity of such an important transcription factor as TFEB must be held in check by a fine-tuned network of proteins, and it was just this network regulating TFEB activity that the researchers identified and described in detail.

One of these regulatory proteins is the enzyme HDAC5. It inhibits the activity of the transcription factor TFEB. As a result, less MuRF1 is generated, thereby reducing the loss of muscle mass. The second enzyme, the protein kinase D1, which is activated by angiotensin II and then migrates into the cell nucleus, mediates the export of the protective enzyme HDAC5 from the cell nucleus and thus activates TFEB expression. This leads to increased formation of MuRF1 and induces the degradation of the muscle protein.

The protein kinase D1 is hence another villain in this process which the researchers studied both in muscle cell cultures and in mice. “With our detailed knowledge of this new signaling pathway and various potential targets, we hope to prevent skeletal muscle atrophy in patients with advanced congestive heart failure,” said Dr. Fielitz.

*Circulation Research, doi: 10.1161/CIRCRESAHA.114.305393

Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression
Philipp Du Bois1, Cristina Pablo Tortola1, Doerte Lodka1, Melanie Kny1, Franziska Schmidt1, Kunhua Song2,3, Sibylle Schmidt1, Rhonda Bassel-Duby3, Eric N. Olson3, Jens Fielitz1
1Department of Molecular Cardiology, Experimental and Clinical Research Center (ECRC), a Cooperation between Max-Delbrück-Centrum and Charité - Universitätsmedizin Berlin, Campus Buch, Berlin, Germany; 2Current address: University of Colorado, Anschutz Medical Campus, Denver, USA, and; 3Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Contact:
Barbara Bachtler
Press Department
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
in the Helmholtz Association
Robert-Rössle-Straße 10
13125 Berlin
Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
e-mail: presse@mdc-berlin.de
http://www.mdc-berlin.de/en

Barbara Bachtler | Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft

More articles from Life Sciences:

nachricht Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute

nachricht Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>