Cardiomyopathies: a protein has been discovered that keeps the heart young

A study funded by Telethon has discovered a protein that enables heart cells to purify themselves of toxic substances and regenerate, thus preventing cardiac diseases. The research project, whose results were published in the Journal of Clinical Investigation, was conducted by researchers at the University of Padua and at the Venetian Institute of Molecular Medicine (VIMM). Read more

Marco Sandri researchIt's called Atrogin-1 and it's a protein that plays an important role in cardiac health: its task, as demonstrated by a study funded by Telethon and conducted by researchers at the University of Padua and the Venetian Institute of Molecular Medicine (VIMM), is to identify and dispose of the waste substances produced by cellular activity, which would be harmful to the heart if allowed to accumulate inside its cells.

In the study published in the Journal of Clinical Investigation, the researchers have shown in animal models that when the protein Atrogin-1 is absent, the disposal mechanism does not work and toxic substances accumulate in the cells of the heart, causing restrictive cardiomyopathy, a disease that has the same characteristics as a rare and severe form of hypertrophic cardiomyopathy.

This disease is characterized by a thickening of the walls of the left ventricle, which can obstruct the flow of blood and also cause fatal cardiac arrhythmias. "The pathology observed, like other more common forms of hypertrophic cardiomyopathy, can be caused by a genetic predisposition or by other factors such as hypertension and ageing," explains Marco Sandri, researcher at the Dulbecco Telethon Institute and associate professor at the University of Padua.

"To date, however, only some of the genes responsible for these diseases are known. For this reason, our having shed light on the role of the Atrogin-1 protein in the onset of cardiomyopathy now creates prospects for a better understanding of the causes of these diseases, some of which are genetic, and the mechanisms involved in the development of cardiac insufficiency. Because the various genetic and acquired forms of hypertrophic cardiomyopathies are far from rare, our having demonstrated the critical role of Atrogin-1 will have a significant impact on the diagnosis, treatment and prevention of these diseases."

The study was conducted at the Venetian Institute of Molecular Medicine (VIMM) by two groups of researchers from the laboratory of molecular epidemiology led by Marco Sandri and the laboratory of molecular cardiology led by Marco Mongillo, a researcher at the University of Padua. The study shows that the protein Atrogin-1 acts in the cells of the heart in the dual role of "sentinel" and "scavenger" of toxic substances. All cells, when they get older and no longer function properly, have the need to regenerate the elements they are composed of and, at the same time, need to dispose of the waste substances they have produced, in order to avoid their build up within the cell and the consequent toxic effects.

Specifically, Atrogin-1 affects two cellular mechanisms for the disposal of these substances. The first is the ubiquitin-proteasome system, which selectively eliminates proteins that have aged and are no longer functional to cellular activity. The second is cell autophagy, which is the process of elimination of other cell components such as mitochondria, several types of damaged organelles and protein aggregates.

"Research has shown that the two mechanisms are not separate and independent, as previously thought, but are linked by the activity of Atrogin-1," explains Marco Mongillo, a researcher at the University of Padua. "Atrogin-1, in fact, is essential to the ubiquitin-proteasome system because it detects and reports the proteins to be replaced. Among these, there is one called CHMP2B, whose identification and replacement is essential for the proper functioning of the second system of ‘cellular cleansing’: autophagy. In practice, we have observed that without Atrogin-1, the two processes of self-cleaning do not work."

In animal models, the researchers noted that the cells' failure to dispose of these substances caused restrictive cardiomyopathy, one of the rarest and most severe forms of hypertrophic cardiomyopathy. The hypothesis, which has already become the subject of further ongoing studies, is that the same mechanism is at the root of the other forms of cardiomyopathies such as those of genetic origin or those caused by other factors such as ageing and hypertension.

The discovery is not only significant for the diagnosis, prevention and understanding of the causes – both genetic and non-genetic causes – of diseases such as hypertrophic cardiomyopathies, which are caused by the accumulation of toxic substances in heart cells, but also because it provides useful indications from the clinical point of view. The study, having helped shed light on the effects of Atrogin-1 inhibition on the onset of cardiomyopathies, opens other prospects for identifying ways to improve the effectiveness of anti-tumour drug therapies, whose side effects include the inhibition of proteasome degradation systems downstream of Atrogin-1.

STUDY PUBLISHED IN THE JOURNAL OF CLINICAL INVESTIGATION, May 1, 2014 Ablation of Atrogin-1 impairs autophagy causing cardiomyopathy and premature death.

Tania Zaglia*1,2, Giulia Milan*3, Aaron Ruhs5, Mauro Franzoso1,2, Enrico Bertaggia3, Nicola Pianca1,2, Andrea Carpi6, Pierluigi Carullo7, Paola Pesce8, David Sacerdoti8, Cristiano Sarais9, Daniele Catalucci7, Marcus Krüger5, Marco Mongillo§ 1,2,4 and Marco Sandri§ 1,3,4,10
1-Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy.
2-Molecular Cardiology and
3-Muscle Signaling lab, Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy.
4-CNR Institute of Neuroscience, Viale G. Colombo3, 35121 Padova,Italy.
5-Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim,Germany.
6-European Institute of Oncology (IEO), Via Adamello 16, 20139 Milano, Italy.
7-National Research Council (CNR), Institute of Genetic and Biomedical Research (IRGB) - UOS of Milan, Milan, Italy and Humanitas Clinical and Research Center, via Manzoni 113, 20089 Rozzano (Milan), Italy.
8-Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy.
9-Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Via Giustiniani 2, 35128 Padua, Italy.
10-Telethon Institute of Genetics and Medicine (TIGEM), via P.Castellino 111, 80131 Napoli, Italy.