(Press-News.org) 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, but the exact mechanism has remained unclear. Now, after seven years of fitting the pieces of this puzzle together, the biologist Dr. Philipp Du Bois and the cardiologist PD Dr. Jens Fielitz of the Experimental and Clinical Research Center (ECRC), a joint cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and the Charité - Universitätsmedizin Berlin in collaboration with the molecular biologist Professor Eric N. Olson (University of Texas Southwestern Medical Center, Dallas, Texas, USA) have elucidated the process and identified new therapeutic targets (Circulation Research doi: 10.1161/CIRCRESAHA.114.305393)*.
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.
INFORMATION:
*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.
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