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GDF11 is a myokine that inhibits muscle differentiation and induces atrophy during regeneration

ABSTRACT: Age-related frailty may in part be due to a decreased competency in skeletal muscle regeneration. The role of the closely related TGFbeta amily molecules myostatin and GDF11 in regeneration is unclear. The commercially available antibody which in a prior report was used to demonstrate an age-related decrease in GDF11 was found to detect both GDF11 and myostatin, and with this reagent it appears that the combination of GDF11 and myostatin increases with age in serum. Mechanistically, GDF11 and myostatin induce SMAD2/3 phosphorylation, and both inhibit myoblast differentiation and regulate identical downstream signaling. GDF11 injected into adult mice in a model of regeneration induces an increase in smaller fibers and a decrease in satellite cell expansion. There are no signs of benefit from GDF11 to regeneration. Thus, GDF11 appears to be an age-associated myokine that inhibits muscle differentiation, and is thus a target for blockade to treat frailty

ORGANISM(S): Homo sapiens

PROVIDER: GSE67326 | GEO | 2015/05/20

SECONDARY ACCESSION(S): PRJNA279519

REPOSITORIES: GEO

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Project description:Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP11) is a member of the Growth differentiation factors (GDFs), a subfamily of proteins belonging to the transforming growth factor-beta (TGF-β) superfamily (Katoh and Katoh 2006). ). In the past 7-8 years, several high profile studies, showed that systemic restoration of GDF11 levels reverses age-related phenotypes and rejuvenated heart and skeletal muscle in aged mice (Loffredo, Steinhauser et al. 2013, Sinha, Jang et al. 2014), improves insulin sensitivity via restoring pancreatic β-cell function in diabetic mice (Li, Li et al. 2017), and increases proliferation of brain capillary endothelial cells thereby improving the vascular and neurogenic rejuvenation in the brain of aged mice (Katsimpardi, Litterman et al. 2014, Finkenzeller, Stark et al. 2015, Zhang, Guo et al. 2018). Nonetheless, the possible rejuvenation effect of GDF11 was questioned over past years by several other studies. These reports doubted the age-associated decrease of circulating GDF11 level and related phenotypes in the muscle, the heart and the brain (Egerman, Cadena et al. 2015, Rodgers and Eldridge 2015); moreover, restoration of GDF11 levels in old mice had no positive effect on heart structure or function (Smith, Zhang et al. 2015). Increase of GDF11 levels had deleterious effects on aging skeletal muscle regeneration (Egerman, Cadena et al. 2015), suggesting also that supraphysiological levels could lead to cachexia (Hammers, Merscham-Banda et al. 2017). In the field of liver diseases, GDF11 was shown to exhibit tumor suppressive properties in HCC cells (Zhang, Pan et al. 2018, Gerardo-Ramírez, Lazzarini-Lechuga et al. 2019) and to worsen hepatocellular injury and liver regeneration after liver ischemia reperfusion injury (Liu, Dong et al. 2018). From these controverted studies, it is clear that the systemic effects of GDF11 in health and disease are not yet clearly and fully delineated. The aim of the present study was to specifically characterize the role of GDF11 in lipid metabolism and in the progression of the NAFLD disease spectrum, which is currently unknown. We thus aimed at investigating the potential effect of GDF11 on lipid droplet formation in human hepatocytes. Our data strongly suggest that GDF11 supplementation exacerbates, both in presence or absence of FFA, lipid droplet accumulation in two hepatic cell models (HepG2 and Hep3B) by impinging on ALK5/SMAD2/3 dependent signaling pathway.

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GDF11 is a myokine that inhibits muscle differentiation and induces atrophy during regeneration

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