Which are the disease mechanisms responsible for inherited cardiomyopathies associated to sudden death?
How to treat such disorders?

Our research aims at identifying the molecular mechanisms underlying familial cardiomyopathies, such as ACM and FHC, both representing leading causes of sudden death in the young population. Our purpose is to recognize novel mechanism-driven therapeutic strategies to counteract disease onset and progression. To reach our goals, we benefit from collaborations with other groups within the VIMM, the clinical Department of Cardiology and other national and international laboratories. In our research, we analyse heart tissue using 2-photon, fluorescence and electron microscopy, biochemical and molecular methods, as well as in vitro model systems to understand the molecular mechanisms of cardiac diseases.

Group Members
Key Publications

Arrhythmogenic Cardiomyopathy (ACM) is a genetically determined cardiac disease, mainly caused by mutations in genes encoding for desmosomal proteins. ACM represents the most frequent cause of sudden death in young athletes. Hearts of ACM patients show cardiomyocyte (CM) death, inflammation and fibro-fatty tissue replacement. The clinical phenotype is characterized by ventricular arrhythmias often triggered by physical stress, such as exercise, which has also been shown to accelerate ACM progression. The pathogenesis of myocardial fibro-fatty remodeling is not yet understood, also because the current experimental models only partially recapitulate the human ACM phenotype.

Familial Hypertrophic Cardiomyopathy (FHC) is the most common genetic disease of the heart, and is mainly caused by mutations in genes encoding for proteins of the sarcomere, the contractile unit of cardiac cells. The disease causes enlargement in the heart size, and manifests with symptoms ranging from weakness and exercise intolerance to severe heart failure and arrhythmias, generally worsening with age. To date, the mechanisms causing FHC are largely undetermined and current therapies are unsuccessful in preventing the progressive cardiac dysfunction. Recently, it has been suggested that the presence in cardiac cells of the incorrect protein, encoded by the mutated gene, overloads the main systems used by cells to remove old and damaged proteins, that is to say, the Ubiquitin Proteasome System (UPS) and the autophagy/lysosome system (ALS), essential in the control of cardiac protein homeostasis.

Which are the disease mechanisms in Arrhythmogenic Cardiomyopathy (ACM)?
One of the main question in ACM concerns the origin of myocardial adipose tissue and several different hypotheses have been proposed. In 2016, our collaborators identified cardiac-mesenchymal stromal cells (C-MSC) as the adipogenic sources in ACM (Sommariva et al. 2016 Eur Heart J). We recently observed that human ACM C-MSC are prone to differentiate into adipocytes, when exposed to sympathetic neurotransmitters. In addition, we observed that desmosomal proteins are expressed by cardiac sympathetic neurons, which densely innervate the myocardium and whose activation has been associated to arrhythmia triggering. The effect of desmosomal mutations on sympathetic neuron physiology will be thus studied both in vivo and in vitro, and the effect of cardiac sympathetic neuron activity on CM and C-MSC physiology will be assessed in co-cultures and in experimental models of ACM generated in our laboratory. Moreover, we will test whether interference with neurogenic signaling, with drugs already in use in clinical trials, may protect from disease onset and sudden death. If successful, the results of this research will contribute to the understanding of ACM pathogenesis and develop novel strategies to target such disease on a more mechanistic background, and prevent cardiac dysfunction and sudden death. Our research will combine histological, immunofluorescence, morphometric, functional, molecular, biochemical and genetic approaches.

Figure 1. Two-photon microscopy allows the 3-D reconstruction of the neuronal network in heart tissue blocks (1 mm3).

Which are the pathogenetic mechanisms underlying Familial Hypertrophic Cardiomyopathy?
We have recently demonstrated that the muscle specific ubiquitin ligase Atrogin1 is a novel regulator of the ALS system, through its target CHMP2B. We also observed that dysfunction in Atrogin1/CHMP2B causes cardiomyopathy. In addition, our recent findings indicate that CHMP2B accumulation and block of autophagy occur in cardiac stress conditions associated to UPS impairment. Based on the literature and on our findings, we aim to elucidate the molecular mechanism whereby CHMP2B accumulation leads to block of autophagy, and to understand whether the impairment in Atrogin1/CHMP2B pathway contributes to FHC progression. We will also search for novel mutations in FHC patients with unknown genetic cause, with the hypothesis that alterations in the UPS/autophagy genes might be primary causes of the disease. Genetic and pharmacological approaches to increase protein quality control will be tested for FHC therapy. Altogether, the results of this project will answer fundamental questions on FHC pathogenesis and contribute to the identification of novel therapies for cardiac dysfunction.

Figure 2. Anomalous accumulation of damaged proteins (red signal) causes sarcomere disarrangement (green signal) and proteotoxic cell death in the heart.

Which is the role of the adrenergic component of the motor nerve in the regulation of skeletal muscle homeostasis and in the pathogenesis of Amyotrophic Lateral Sclerosis?
An additional research line, on-going in our laboratory, focuses on the mechanisms of muscle atrophy and neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). This latter question applies recent discoveries on the role of sympathetic neurons in the control of cardiac cell structure (Zaglia et al. 2013 Cardiovasc Res; Zaglia & Mongillo 2017 J Physiol), to the study of skeletal muscle diseases. ALS is a neurodegenerative disorder affecting the viability of motor neurons (MNs), which control skeletal muscle contraction. ALS patients display muscle weakness, paralysis and, ultimately, respiratory failure. The researchers’ efforts are focused on the elucidation of ALS pathogenesis and the identification of novel therapeutic strategies to counteract the disease progression. Recently, the β2-adrenoceptor (β2-AR) agonist, clenbuterol, has been shown to reduce muscle atrophy and MN degeneration in ALS patients. However, β-AR agonists lead to cardiac side effects, and it is still debated whether clenbuterol affects the well-being of MNs directly or via amelioration of muscle trophism. The motor nerves, innervating skeletal muscles, contain a large amount of noradrenaline-releasing sympathetic neurons (SNs), interacting with myocyte sarcolemma at the neuromuscular junction, where β2-ARs concentrate. The role of the SNs of the motor nerve is still largely undetermined. Based on the data obtained in parallel studies, in the heart, we hypothesize that the intercellular communication between SNs, skeletal myocytes and MN has a key role in skeletal muscle physiology and ALS pathogenesis. We will use optogenetics to selectively control the adrenergic component of the motor nerve while monitoring muscle cAMP levels, and evaluating the UPS and autophagy state, to determine the role of sympathetic neurons on the innervated muscles and ALS progression. This project has the potential to improve the knowledge on muscle neurobiology, and to pose the bases for further mechanistic studies.

Valentina Prando

PhD student


Anna Di Bona

PhD student


Silvia Bertoli


Arianna Scalco

Master Student


Veronica Vita



  1. T. Zaglia, P. Ceriotti, A. Campo, G. Borile, A. Armani, P. Carullo, V. Prando, R. Coppini, V. Vida, TO. Stølen, W. Ulrik, E. Cerbai, G. Stellin, G. Faggian, D. De Stefani, M. Sandri, R. Rizzuto, F. Di Lisa, T. Pozzan, D. Catalucci, M. Mongillo. Content of mitochondrial calcium uniporter (MCU) in cardiomyocytes is regulated by microRNA-1 in physiologic and pathologic hypertrophy. Proc Natl Acad Sci U S A. 114(43):E9006-E9015 (2017). doi: 10.1073/pnas.1708772114.
  2. T. Zaglia‡, M. Mongillo‡. ‡corresponding authors. Cardiac sympathetic innervation, from a different point of (re)view. J Physiol. 595(12):3919-3930 (2017). doi: 10.1113/JP273120.
  3. N. Pianca, T. Zaglia, M. Mongillo M. Will cardiac optogenetics find the way through the obscure angles of heart physiology? Biochem Biophys Res Commun. 482(4):515-523 (2017). doi: 10.1016/j.bbrc.2016.11.104.
  4. T. Zaglia‡, A. Di Bona, T. Chioato, C. Basso, S. Ausoni, M. Mongillo. ‡ corresponding author. Optimized protocol for immunostaining of experimental GFP-expressing and human hearts. Histochem Cell Biol. 146(4):407-19 (2016). doi: 10.1007/s00418-016-1456-1.
  5. T. Zaglia, N. Pianca, G. Borile, F. Da Broi, C. Richter, M. Campione, SE. Lehnart, S. Luther, D. Corrado, L. Miquerol, M. Mongillo. Optogenetic determination of the myocardial requirements for extrasystoles by cell type-specific targeting of ChannelRhodopsin-2. Proc Natl Acad Sci U S A. 112(32):E4495-504 (2015). doi: 10.1073/pnas.1509380112.
  6. T. Varanita, ME. Soriano, V. Romanello, T. Zaglia, R. Quintana-Cabrera, M. Semenzato, R. Menabò, V. Costa, G. Civiletto, P. Pesce, C. Viscomi, M. Zeviani, F. Di Lisa, M. Mongillo, M. Sandri, L. Scorrano L. The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage. Cell Metab. 21(6):834-44 (2015). doi: 10.1016/j.cmet.2015.05.007.
  7. A. Castaldi*, T. Zaglia*, V. Di Mauro, P. Carullo, G. Viggiani, G. Borile, B. Di Stefano, GG. Schiattarella, MG. Gualazzi, L. Elia, GG. Stirparo, ML. Colorito, G. Pironti, P. Kunderfranco, G. Esposito, ML. Bang, M. Mongillo, G. Condorelli, D. Catalucci. MicroRNA-133 modulates the β1-adrenergic receptor transduction cascade. Circ Res. 115(2):273-83 (2014). doi: 10.1161/CIRCRESAHA.115.303252.
  8. T. Zaglia, G. Milan, A. Ruhs, M. Franzoso, E. Bertaggia, N. Pianca, A. Carpi, P. Carullo, P. Pesce, D. Sacerdoti, C. Sarais, D. Catalucci, M. Krüger, M. Mongillo, M. Sandri. Atrogin-1 deficiency promotes cardiomyopathy and premature death via impaired autophagy. J Clin Invest. 124(6):2410-24 (2014). doi: 10.1172/JCI66339.
  9. T. Zaglia, G. Milan, M. Franzoso, E. Bertaggia, N. Pianca, E. Piasentini, VA. Voltarelli, D. Chiavegato, PC. Brum, DJ. Glass, S. Schiaffino, M. Sandri, M. Mongillo. Cardiac sympathetic neurons provide trophic signal to the heart via β2-adrenoceptor-dependent regulation of proteolysis. Cardiovasc Res. 97(2):240-50 (2013). doi: 10.1093/cvr/cvs320.
  10. J. van Hengel, M. Calore, B. Bauce, E. Dazzo, E. Mazzotti, M. De Bortoli, A. Lorenzon, IE. Li Mura, G. Beffagna, I. Rigato, M. Vleeschouwers, K. Tyberghein, P. Hulpiau, E. van Hamme, T. Zaglia, D. Corrado, C. Basso, G. Thiene, L. Daliento, A. Nava, F. van Roy, A. Rampazzo. Mutations in the area composita protein αT-catenin are associated with arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 34(3):201-10 (2013). doi: 10.1093/eurheartj/ehs373.


  • PhD: Dept. of Pathological Anatomy, University of Padova, Italy (2007)
  • Postdoc: Dept. of Biomedical Sciences, University of Padova, Italy (2007-2011)
  • Research Fellowship: Venetian Institute of Molecular Medicine, Padova, Italy (2011-2013)
  • Telethon Junior Researcher: Venetian Institute of Molecular Medicine, Padova, Italy (2013-2016)
  • Assistant Professor: Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Italy (since 2017)
  • Junior Principal Investigator: Venetian Institute of Molecular Medicine, Padova, Italy (since 2017)

Selected Awards

  • 2016 – Best poster presentation. FCVB (ESC), Florence
  • 2012 – Young Investigator Award, Heart Failure (ISHR), Belgrade
  • 2012 – Best poster presentation. FCVB (ESC), London