Molecular Cardiology · AG Eden / FreyDepartment of Internal Medicine III · Cardiology, Angiology and Pneumology
AG Eden / Frey

Research

Our lab investigates intracellular signaling pathways that regulate cardiac hypertrophy and heart failure. We combine molecular biology, phosphoproteomics, and advanced cardiomyocyte models to understand disease mechanisms and identify novel therapeutic targets.

  1. 01

    STRIPAK Signaling

    Our group identified Myoscape (STRIP2) as a cardiac-specific component of the STRIPAK complex that regulates L-type calcium channel surface expression, thereby controlling cardiac calcium homeostasis and contractility (Eden et al., Nat Commun 2016). Recently, we demonstrated that the STRIPAK-associated kinase MST4 regulates cardiomyocyte growth and survival and is upregulated in human cardiomyopathy (Eden et al., J Biol Chem 2024). Additionally, we investigate protein interaction networks involving the BLOC-1 complex and Dysbindin that modulate STRIPAK signaling in the heart (Borlepawar et al., Cells 2020).

    Myoscape/STRIP2 · MST4 · L-type Ca²⁺ channel · Dysbindin · BLOC-1
    Myoscape and MST4 at the cardiac STRIPAK complexIllustration: section of a cardiomyocyte with sarcolemma, T-tubule and intercalated disc. Myoscape (STRIP2), a heart-specific component of the STRIPAK complex, binds directly to the L-type Ca²⁺ channel Cav1.2. The STRIPAK-associated kinase MST4 (STK26) localizes to the intercalated disc.SARCOLEMMA · T-TUBULECav1.2Ca²⁺binds directlyMyoscapeSTRIP2STRIPAKcomplexINTERCALATEDDISCMST4STK26AI-generated illustration
    Fig. 1 · IllustrationMyoscape and MST4 at the cardiac STRIPAK complex

    Myoscape (STRIP2), a heart-specific STRIPAK component, binds the L-type Ca²⁺ channel Cav1.2 directly and regulates its surface expression, and thereby Ca²⁺ cycling and contractility.

    MST4 (STK26), a STRIPAK-associated kinase at the intercalated disc, promotes cardiomyocyte growth and survival and is upregulated in human cardiomyopathy.

    Image layer AI-generated (GPT Image 2.5); labels and content after Eden et al., Nat Commun 2016, and Eden et al., J Biol Chem 2024. Not to scale.

  2. 02

    M-Band Signaling

    We identified Myomasp/LRRC39 as a heart- and muscle-specific protein that constitutes a novel component of the sarcomeric M-band involved in mechanical stretch sensing (Will, Eden et al., Circ Res 2010). In parallel, we showed that cardiac overexpression of the intercalated disc protein Myozap causes a protein-aggregate-associated cardiomyopathy (Frank, Rangrez, Eden et al., J Mol Cell Cardiol 2014), while Myozap deficiency promotes adverse cardiac remodeling through differential regulation of MAPK/SRF and β-catenin/GSK-3β signaling (Rangrez, Eden et al., J Biol Chem 2016).

    Myomasp/LRRC39 · Myozap · MAPK/SRF · β-catenin/GSK-3β
    Myomasp at the sarcomeric M-bandIllustration: one sarcomere with Z-discs at both ends, overlapping thick and thin filaments and the M-band in the center, with the nucleus below. Myomasp (LRRC39) sits at the M-band on the MYH7 thick filaments; SRF is shown bound to DNA in the nucleus.Z-DISCZ-DISCM-BANDMYH7thick filamentsMyomaspLRRC39SRFNUCLEUSAI-generated illustration
    Fig. 2 · IllustrationMyomasp at the sarcomeric M-band

    Myomasp (LRRC39), a heart- and muscle-specific protein, localizes to the sarcomeric M-band and binds the C-terminus of myosin heavy chain MYH7.

    Its knockdown in neonatal rat cardiomyocytes suppresses serum response factor-dependent gene expression dose-dependently, lowers MYH7 and myomesin-1 and -2, and reduces force generation in engineered heart tissue.

    Image layer AI-generated (GPT Image 2.5); labels and content after Will et al., Circ Res 2010. Not to scale.

  3. 03

    Stretch Sensing

    Our research investigates how cardiomyocytes sense mechanical load and translate it into cellular responses. We characterized Myomasp/LRRC39 as a sarcomeric mechanosensor at the M-band that detects stretch stimuli (Will, Eden et al., Circ Res 2010). Through Myoscape/STRIP2, we elucidated a mechanism by which mechanical signals regulate L-type calcium channel surface expression and thereby excitation-contraction coupling (Eden et al., Nat Commun 2016). Furthermore, we explore the role of Filamin C in cardiac filaminopathies and its divergent significance for human cardiomyopathies (Eden & Frey, J Clin Med 2021).

    Myomasp · Myoscape · Filamin C · EC coupling · T-tubule
    Mechanical signals at the M-band, Z-disc and dyadIllustration: a myofibril with two sarcomeres under stretch, above it the sarcolemma and a T-tubule with apposed sarcoplasmic reticulum (dyad). Labelled are myomasp at the M-band, filamin C at the Z-disc, and myoscape and Cav1.2 at the dyad.SARCOLEMMA · T-TUBULEDYADCav1.2MyoscapeSTRIP2Z-DISCFilamin CM-BANDMyomaspSTRETCHAI-generated illustration
    Fig. 3 · IllustrationMechanical signals at the M-band, Z-disc and dyad

    M-band: myomasp (LRRC39) is involved in stretch sensing; its knockdown upregulates the stretch-sensitive genes GDF-15 and BNP.

    Z-disc: filamin C (FLNC); mutations were first linked to myofibrillar myopathy and are increasingly found in various forms of cardiomyopathy.

    Dyad: myoscape (STRIP2) binds the L-type Ca²⁺ channel Cav1.2 directly and regulates its surface expression and thereby excitation–contraction coupling.

    Image layer AI-generated (GPT Image 2.5); labels and content after Will et al., Circ Res 2010; Eden & Frey, J Clin Med 2021 (review); Eden et al., Nat Commun 2016. Not to scale.

  4. 04

    Cardiac Hypertrophy

    The Calcineurin-NFAT signaling axis is a central research focus of our group. With the discovery of Calsarcins as sarcomeric calcineurin-binding proteins (Frey et al., PNAS 2000) and the demonstration that Calsarcin-1 deficiency sensitizes calcineurin signaling and accelerates pathological hypertrophy (Frey et al., Nat Med 2004), we defined a novel regulatory mechanism. Calsarcin-2 deficiency, in contrast, increases exercise capacity via Calcineurin/NFAT activation (Frey et al., J Clin Invest 2008). We further showed that SUMO2 activates Calcineurin-NFAT signaling in a sumoylation-independent manner, thereby promoting cardiomyocyte hypertrophy (Bernt, Rangrez, Eden et al., Sci Rep 2016). Currently, we are investigating metabolic approaches: AAV-mediated CPT1B overexpression protects against hypertrophy and heart failure in a murine pressure overload model (Kliesow Remes et al., Basic Res Cardiol 2025).

    Calsarcin-1/2 · Calcineurin-NFAT · SUMO2 · CPT1B · AAV gene therapy
    Calsarcins and calcineurin–NFAT signalingIllustration: the Z-disc of a hypertrophied heart muscle cell with anchored calsarcins and calcineurin, transcription factors in the cytosol and one factor entering the nucleus through a nuclear pore.Z-DISCCalsarcin-1MYOZ2CalcineurinNFATNUCLEUSAI-generated illustration
    Fig. 4 · IllustrationCalsarcins and calcineurin–NFAT signaling

    Calsarcins bind calcineurin and tether it to α-actinin at the Z-disc.

    Calsarcin-1 (MYOZ2) restrains calcineurin: without it, calcineurin signaling is enhanced, a hypertrophic gene program is activated and the cardiac growth response to pressure overload is increased (mouse).

    Calsarcin-2 (MYOZ1), expressed exclusively in fast-twitch skeletal muscle, inhibits calcineurin; knockout mice show more NFAT activity, more slow oxidative fibers and greater running capacity.

    SUMO2 binds the catalytic subunit of calcineurin directly, promotes its nuclear localization and cardiomyocyte hypertrophy, independently of sumoylation.

    AAV-mediated CPT1B overexpression attenuates hypertrophy, fibrosis and systolic dysfunction after pressure overload (mouse, TAC) and phenylephrine-induced hypertrophy of neonatal rat cardiomyocytes.

    Image layer AI-generated (GPT Image 2.5); labels and content after Frey et al., PNAS 2000; Frey et al., Nat Med 2004; Frey et al., J Clin Invest 2008; Bernt et al., Sci Rep 2016; Kliesow Remes et al., Basic Res Cardiol 2025. Not to scale.