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Archives of cardiovascular diseases
Volume 108, n° 8-9
pages 409-411 (août 2015)
Doi : 10.1016/j.acvd.2015.08.001
Received : 7 August 2015 ;  accepted : 10 August 2015
A member of the TGF-β superfamily, GDF11: functions in the cardiac regeneration, perhaps an “elixir of youth?”
Un membre de la superfamille des TGF-β, le GDF11 : ses fonctions dans la régénération cardiaque, peut-être un « elixir de jeunesse » ?
 

Yves Cottin a, b, Luc Rochette a,
a Laboratoire de physiopathologie et pharmacologies cardio-métaboliques (LPPCM), 21000 Dijon, France 
b Service de cardiologie, CHU de Dijon, Inserm UMR866, facultés des sciences de santé, université de Bourgogne, 21000 Dijon, France 

Corresponding author.

Keywords : GDF11, Heart, Cardiac regeneration

Mots clés : GDF11, Cœur, Régénération cardiaque


The transforming growth factor (TGF)-β superfamily of secreted factors comprises more than 30 members including activins, nodals, bone morphogenetic proteins (BMPs), and growth differentiation factors (GDFs) such as GDF11 and GDF15. The regulation of members of the TGF-β superfamily is composite, because many proteins that can bind the ligands and inhibit their activities have been identified [1]. Signalling by TGF-β family ligands is essential for the regulation of multiple processes during vertebrate development, tissue homeostasis and tissue repair. Mechanisms by which TGF-β may maintain cellular homeostasis is through the induction of cytoprotective proteins such as heme-oxygenases-1 (HO-1) and/or interaction with NADPH-oxydases or nitric oxide synthases. The HOs are rate-limiting enzymes that catalyse the conversion of heme into carbon monoxide, free iron and biliverdin, which is subsequently converted to bilirubin by biliverdin reductase. The products of the HO reaction modulate important adaptive responses to oxidative stress, inflammation and cardiovascular functions [2]. Studies demonstrated that TGF-β plays an important role in the pathogenesis of the infarcted heart due to inflammatory and reparative response modulation [3]. Members of the TGF-β superfamily exert their effects by binding to specific serine/threonine kinase type I and type II receptor complexes. These receptors, known as TGF-β type I and type II receptors, are produced from precursor proteins by proteolytic processing. After cleavage of a single peptide bond by a furin-type protease, the N-terminal propeptide and the disulphide-bonded homodimer containing the mature growth factor domains remain associated, forming an inactive complex known as the latent complex. The active mature growth factors may be liberated from the latent complexes through degradation of the propeptide by a variety of proteases [4].

GDF11 (comprising 407 amino-acids) is a member of the TGF-β superfamily that regulates diverse cellular processes. GDF11 has been measured in different tissues. It is expressed in the pancreas, intestine, kidney, skeletal muscle, heart and developing nervous system, olfactory system and retina [5]. Its expression is most abundant in young adult organs and seems to decrease during aging. Recently, the results of new study clearly demonstrated that GDF11 serum levels do not decrease, and instead increase during aging [6]. It is evoked that the reagents used in some studies are not GDF11 specific, as they also pick up myostatin, the amino acid sequence of GDF11 being 90% identical to that of myostatin.

Aging is characterized by a gradual functional decline of all organ systems. The concept of the heart as a terminally differentiated organ incapable of replacing damaged myocytes has been at the centre of cardiovascular research and therapeutic development. The progressive decline in myocyte number with aging is demonstrated. Among all aging theories, one describes nitro-oxidative stress associated with the overproduction of reactive oxygen species and reactive nitrogen species due mainly to the presence of chronic, low-grade inflammation. Extensive preclinical and clinical trials have investigated a number of cell types for cardiac regeneration including skeletal myoblasts, mesenchymal stem cells, embryonic stem cells and cardiac stem cells. Although most cell types had produced promising results in both in-vitro and preclinical studies, they were disappointing in terms of clinical benefits [7].

In a very interesting new study, GDF11 was shown to be a circulating negative regulator of cardiac hypertrophy, suggesting that raising GDF11 levels could potentially treat or prevent age-related cardiac hypertrophy [8]. Recent specific experimental approaches using techniques of parabiosis indicate that impaired regeneration in aged mice is reversible by exposure to “young” circulation. It was demonstrated that GDF11 systemically regulates heart and muscle aging, suggesting that young blood contains humoral “rejuvenating” factors that can restore regenerative function. In a surgical procedure, the circulatory system of a young animal is coupled to that of an aged animal. This procedure can rejuvenate a number of organs in the older of the pair. The technique refers to the condition in which two entire living animals are joined surgically and develop a single, shared circulatory system. It was first introduced by the French physiologist Paul Bert in the 1860s. The surgical procedure involves generating skin incisions extending along the adjoining flanks of two animals (usually mice) and suturing adjacent skin flaps between the animals. In current protocols, the incisions typically extend along the whole body flank. The peritoneum is incised and sutured together between the animals to form a common peritoneal cavity. The first studies started to graft animals of different ages to each other (heterochronic parabiosis) in order to investigate effects induced through exposure of an aged organism to a youthful systemic environment. Heterochronic parabiosis, the parabiotic pairing of two animals of different ages, provides an experimental system to test for systemic effects on the process of cell and tissue aging. Accumulating evidence has indicated that the blood of young animals contains powerful “factors of youth”. Loffredo et al. [8] generated parabiotic pairs of young with old (heterochronic) mice and compared their heart sizes with those of parabiotic pairs of mice of the same age (isochronic) and those of age-matched controls that did not undergo parabiosis. After only 4 weeks, cardiac hypertrophy was reversed in the old heterochronically paired mice. The authors identified that the myocyte cross-sectional area was decreased in aged mice paired with younger adult mice. These results are consistent with the loss of youthful factors that restrict myocyte size in the aged systemic environment rather than the accumulation of hypertrophic factors during aging. The authors compared concentrations of molecules found in the circulation of old versus young mice using a proteomic approach and showed that levels of GDF11 were constantly lower in aged than in younger adult plasma. To demonstrate that GDF11 was a negative regulator of cardiac myocyte hypertrophy, these authors injected recombinant GDF11 daily for 30 days in aged mice using a blinded, randomized study design. Heart weight and cardiomyocyte area were reduced without affecting cardiac function.

In summary, GDF11 appears to be a modulator of age-related cardiac hypertrophy. The identification of GDF11 as a “rejuvenating factor” therefore opens up perspectives for the treatment of age-related cardiac dysfunction. It is suggested that GDF11 “supplementation” in older patients may offer a new approach for the treatment of some cardiac and skeletal diseases. Recent data indicate that GDF11 systemically regulates muscle aging and may be therapeutically useful for reversing age-related skeletal muscle and stem cell dysfunction [9]. Now, evidence of brain rejuvenation exists and GDF11 has been reported to increase the generation of neurons in aged mice [10]. The mythical fountain of youth has a long history in human imagination. American author Mark Twain, who died of a heart attack, noted during his twilight years that “life would be infinitely happier if we could only be born at the age of 80 and gradually approach 18.”

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

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