Experimental and Clinical Research Center

Fielitz Lab

Protein regulation in heart and skeletal muscle


Our translational research group focuses on disease mechanisms, which might eventually be useful to develop novel treatment strategies. In particular, we are studying mechanisms of pathological cardiac remodeling and inflammation-dependent skeletal muscle failure.

We are particularly interested in the ubiquitin proteasome system (UPS). We showed earlier that muscle RING finger (MuRF) 1 and MuRF3 are important for maintaining cardiac and skeletal muscle structure and function. We are currently identifying and characterizing the regulation and function of MuRF proteins in myocytes. We identified the stress responsive serine/threonine kinase protein kinase D1 (PKD1) as an important regulator of pathological cardiac remodeling and fiber type specification in skeletal muscle. We investigated PKD1-dependent control of the class IIa histone deacetylase/myocyte enhancer factor-2 axis in chronic cardiac stress situations, and work on non-transcriptional functions of PKD1 in heart and skeletal muscle.


Group Leader

Prof. Dr. med. Jens Fielitz

Phone: +49 (30) 450 540424 /- 421
Fax:    +49 (30) 450 540928



Dr. rer. nat. Dörte Lodka

Phone: +49 (30) 450 540578 /- 428


Dr. rer. nat. Melanie Kny

Phone: +49 (30) 450 540578 /- 428


Technical Assistants

Sibylle Schmidt

Phone: +49 (30) 450 540 424 /- 422


PhD students

Alexander Hahn

Phone: +49 (30) 450 540578 /- 428


Cristina Pablo

Phone: +49 (30) 450 540 428


Medical doctoral candidates

Katharina Busch

Phone: +49 (30) 450 540 428


Julius Grunow

Phone: +49 (30) 450 540 428


Sebastian Wundersitz

Phone: +49 (30) 450 540 428


Lukas Zanders

Phone: +49 (30) 450 540 428


Master students

Sarah Bützow


Falk Fischer

Phone: +49 (30) 450 540 428



Research Projects

Maintenance of muscular structure and function requires a precise control of protein synthesis and degradation; abnormalities in these processes can give rise to myopathies. The ubiquitin proteasome system (UPS) is largely responsible for the degradation of long-lived proteins, such as components of the contractile apparatus of striated muscle cells. The UPS is activated during cardiac hypertrophy, heart failure and skeletal muscle atrophy leading to degradation of structural and contractile proteins, most notably myosin heavy chain, resulting in a reduction of cardiac and muscle function. Within the UPS E3 ubiquitin ligases mediate substrate specificity and are the rate limiting enzymes. We investigate the regulation and function of the muscle-specific E3 ubiquitin ligases Muscle RING-finger (MuRF) 1, 2 and 3 in myocyte remodeling. We showed that muscle RING finger (MuRF) 1, 2 and MuRF3 are important for maintaining cardiac and skeletal muscle structure and function. Combined deletion of MuRF1 and MuRF3, and MuRF2 and MuRF3 resulted in protein aggregate myopathy of the heart and skeletal muscle. Nevertheless, the function of MuRF proteins in muscle cells is not well understood. Therefore, we are currently identifying and characterizing the regulation and function of MuRF proteins in greater detail. 
Protein homeostasis is also impaired in muscle of critically ill patients. We reported an imbalanced protein homeostasis with decreased synthesis and increased degradation of muscular proteins in muscle of patients with Intensive Care Unit (ICU)-acquired weakness (ICUAW; a major comorbidity of critically ill patients). Although, inflammation is thought to be involved in the pathogenesis of ICUAW the precise disease mechanisms are not well understood.
We identified the stress responsive serine/threonine kinase protein kinase D1 (PKD1) as an important regulator of pathological cardiac remodeling and Ang II-induced muscle wasting. We described PKD1-dependent control of the class IIa histone deacetylase 5/transcription factor EB (TFEB) axis in muscle atrophy, and work on non-transcriptional functions of PKD1 in heart and skeletal muscle.

Function of PKD1 in Ang II-induced muscle wasting

Function of the stress-dependent kinase Protein Kinase D1 (PKD1) in angiotensin II (Ang II) induced muscle atrophy

Skeletal muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure. The molecular mechanisms are imperfectly understood, although an activated renin–angiotensin aldosterone system has been implicated. Angiotensin (Ang) II induces skeletal muscle atrophy in part by increased muscle-enriched E3 ubiquitin ligase muscle RING-finger-1 (MuRF1/Trim63) expression, which may involve protein kinase D1 (PKD1). In a recent study we elucidated the molecular mechanism of Ang II–induced skeletal muscle wasting. In a cDNA expression screen we identified the lysosomal hydrolase-coordinating transcription factor EB (TFEB) as novel regulator of the human MuRF1/Trim63 promoter. TFEB played a key role in regulating Ang II–induced skeletal muscle atrophy by transcriptional control of MuRF1/Trim63 via conserved E-box elements. Inhibiting TFEB with small interfering RNA prevented Ang II–induced MuRF1/Trim63 expression and muscle atrophy. The histone deacetylase-5 (HDAC5), which was directly bound to and colocalized with TFEB, inhibited TFEB-induced MuRF1/Trim63 expression. The inhibition of TFEB by HDAC5 was reversed by PKD1, which was associated with HDAC5 and mediated its nuclear export. Mice lacking PKD1 in skeletal myocytes were resistant to Ang II–induced muscle wasting. In our study we proposed that elevated Ang II serum concentrations, as occur in patients with congestive heart failure, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting. Now we are working on further molecular mechanisms involved in this signalling pathway..

Regulation of function and activity of Muscle RING-finger (MuRF) proteins ​

The Muscle RING-finger (MuRF) Protein Family of E3 Ligases

Striated muscle structure and function is maintained by precise control of protein synthesis and degradation; abnormalities in these processes can give rise to myopathies. The UPS degrades misfolded proteins. UPS substrate specificity is mediated by E3 ligases, such as RING-finger proteins. Muscle RING-finger (MuRF) proteins 1, 2, and 3 comprise a subfamily of the RING-finger E3 ubiquitin ligases that are specifically expressed in the heart and skeletal muscle. We generated MuRF3 knockout mice and demonstrated that MuRF3 is involved in maintaining cardiac structure and function, and the integrity of the ventricular wall following acute myocardial infarction. Additionally, we found that MuRF1–/–/MuRF3–/– double mutant (DKO) mice display a distinct cardiac and skeletal muscle protein aggregate myopathy. Cardiac and skeletal muscles of DKO mice displayed a striking subsarcolemmal accumulation of myosin (MyHC) accompanied by cardiac hypertrophy, decreased cardiac function and reduced maximal force development of the skeletal muscle (Figure 1). MuRF1 and MuRF3 interact specifically with ?/slow MyHC and MyHCIIa and utilize UbcH5a, -b, and -c as E2 ubiquitin–conjugating enzymes to catalyze the ubiquitinylation and degradation of these proteins. In addition, we generated and phenotypically characterized MuRF2–/–/MuRF3–/– DKO mice. MuRF2–/–/MuRF3–/– DKO mice also showed a protein aggregate myopathy in skeletal muscle. Maximal force development was reduced in DKO skeletal muscle. In addition, a fibre type shift towards slow/type I fibres occurred in MuRF2–/–/MuRF3–/– DKO soleus and extensor digitorum longus. MuRF2–/–/MuRF3–/– DKO hearts showed decreased systolic and diastolic function. Further analyses revealed an increased expression of the MyHC isoform beta/slow and disturbed calcium handling as potential causes for the phenotype in MuRF2–/–/MuRF3–/– DKO hearts. Our data show that all members of the MuRF family have partially redundant functions which are important for maintenance of skeletal muscle and cardiac structure and function in vivo. We are now working on the regulation of function and activity of MuRF proteins.

Inflammation-dependent skeletal muscle failure

Inflammation-induced skeletal muscle failure in critically ill patients

Clinical data suggested that sepsis and systemic inflammation are major risk factors for ICUAW and CIM and increased serum levels of inflammatory cytokines might induce muscle atrophy in critically ill patients. We reported that the inflammatory cytokine interleukin-6 (IL6) is continuously increased in muscle during inflammation and associated with muscle failure. Increased IL6 expression in muscles of critically ill patients was indicative for inflammation directly occurring in muscle. We reported that inflammation causes acute-phase response (APR) directly in skeletal muscle of critically ill patients. The APR protein serum amyloid A (SAA) 1 was increased in the skeletal muscle of CIM patients were it accumulated in the interstitium, around myofibers. Increased SAA1 expression was inversely correlated with excitability of muscle membranes indicating that SAA1 plays a role in muscle function. We showed that differentiated human and murine myocytes synthesize SAA1, and that SAA1 synthesis was increased by inflammatory cytokines (i.e. IL6, TNF?). Importantly, both IL6 and SAA1 induce atrophy by increasing protein degradation in muscle of patients and rodents. Together, our data indicated that inflammation induces APR directly in muscle possibly contributing to ICUAW. However, the mechanisms how inflammatory cytokines and APR proteins mediate muscle atrophy, and the receptors and signaling pathways involved in this process are unknown.

Figure 1. We show the effects of cardiomyocyte specific PKD1 elimination. After angiotensin II (Ang II) treatment, PKD1 mutant mice (cKO) displayed less cardiac hypertrophy and a reduction in perivascular and interstitial fibrosis (hematoxylin and eosin and Masson's trichrome stainings; top panel). Atrial natriuretic factor (ANF), ß-myosin heavy chain (β-MHC), and procollagen, type I, α2 (Col1α2) expression was also compromised in PKD1 mutant mice (cKO) (bottom panel).



Cooperations, Funding and Job offers

Cooperation partners

Cooperations at the Max Delbrück Center for Molecular Medicine (MDC), Belin, Germany

•Prof. Dr. Thomas Sommer - Intracellular Proteolysis

•Prof. Dr. Michael Bader - Molecular Biology of Peptide Hormones

•Prof. Dr. Carmen Birchmeier  - Developmental Biology / Signal Transduction


Cooperations at the Experimental and Clinical Research Center (ECRC), Berlin, Germany

•Dr. med. Michael Boschmann - Clinical Reseach Unit


Cooperation with our other partners

•PD Dr. Steffen Weber-Carstens, Klinik für Anästhesiologie mit Schwerpunkt operative Intensivmedizin der Charité - Universitätsmedizin Berlin, Berlin, Germany

•Prof. Dr. Hortense Slevogt, Universitätsklinikum Jena, Zentrum für Innovationskompetenz Septomics; Jena, Germany

•Prof. Dr. Kai Kappert, Center for Cardiovascular Research (CCR), Charité - Universitätsmedizin Berlin, Berlin, Germany

•Prof. Dr. Gunnar Dittmar, Luxembourg Institute of Health, Luxembourg

•Prof. Dr. Oliver Müller, Klinik für Kardiologie, Angiologie und Pneumologie, Innere Medizin III, Heidelberg, Germany

•Prof. Dr. Theresia Kraft, Institut für Molekular- und Zellphysiologie, Physiologie, Medizinische Hochschule Hannover, Germany

•PD Dr. Renate Scheibe, Institute for Physiological Chemistry, Gene regulation in cardiomyocytes and in skeletal muscle, Medizinische Hochschule Hannover, Germany

•Prof. Dr. Siegfried Labeit, Department of Integrative Pathophysiology, Universitätsmedizin Mannheim, University of Heidelberg



  • Berlin Institute of Health (BIH)
  • Charité-Universitätsmedizin Berlin
  • Deutsche Forschungsgemeinschaft (DFG)
  • Deutsches Zentrum für Luft und Raumfahrt e. V. (DLR) and European Space Agency (ESA)
  • Max Delbrück-Centrum für Molekulare Medizin (MDC)


Job offers

People with brilliant ideas and commitment are always welcome to apply.

We have open positions for master's students and medical doctoral candidates.

Please contact Jens Fielitz for more information.

Dr. Jens Fielitz

Prof. Dr. Jens Fielitz




Experimental and Clinical Research Center
Lindenberger Weg 80
13125 Berlin