Pathophysiological levels of GDF11 activate Smad2/Smad3 signaling and induce muscle atrophy in human iPSC-derived myocytes

Abstract

Skeletal muscle mass is negatively regulated by several TGF-β superfamily members. Myostatin (MSTN) is the most prominent negative regulator of muscle mass. Recent studies show that in addition to MSTN, GDF11, which shares high sequence identity with MSTN, induces muscle atrophy in vitro and in vivo at supraphysiological levels, whereas controversy regarding its roles exists. Furthermore, higher circulating GDF11 levels associate with frailty in humans. On the other hand, little is known about the effect of pathophysiological levels of GDF11 on muscle atrophy. Here we seek to determine whether pathophysiological levels of GDF11 are sufficient to activate Smad2/Smad3 signaling and induce muscle atrophy using human iPSC-derived myocytes (hiPSC-myocytes). We first show that incubating hiPSC-myocytes with pathophysiologic concentrations of GDF11 significantly reduces myocyte diameters. We next demonstrate that pathophysiological levels of GDF11 are sufficient to activate Smad2/3 signaling. Finally, we show that pathophysiological levels of GDF11 are capable of inducing the expression of Atrogin-1, an atrophy-promoting E3 ubiquitin ligase and that FOXO1 blockage reverses the GDF11-induced Atrogin-1 expression and atrophic phenotype. Collectively, our results suggest that GDF11 induces skeletal muscle atrophy at the pathophysiological level through the GDF11-FOXO1 axis.

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“…Metformin also exhibits anti-inflammatory and antioxidative properties, improves satellite cell viability and regenerative effects, and promotes myofibrillar repair [ 108 , 109 , 110 ]. The mechanism by which metformin improves muscle repair could be attributable to the drug-induced attenuation of Smad 2 and 3 activities in the context of the TGF-β signaling pathway [ 111 ], as the attenuation of this pathway stimulates insulin secretion and myofibrillar synthesis [ 112 , 113 ]. On the other hand, metformin affects the AMPK/mTORc1 pathway, thus reducing glucose output from the liver and fasting glucose levels.…”

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“…10 . Fbox1 and MuRF-1 are atrophy-associated ubiquitin ligases involved in ubiquitin-mediated proteolysis [33] , and GDF-8 is the most prominent negative regulator of skeletal muscle mass [34] . Pfn1 and Pycr3 play critical roles in skeletal muscle development.…”

Myofiber Baf60c controls muscle regeneration by modulating Dkk3-mediated paracrine signaling

“…Notably, Gdf11 has gained more attention in the last decade due to numerous reports demonstrating its functions in multiple systems, such as skeletal muscle, cardiac myocyte, and bone homeostasis, with inconsistent or even controversial results ( Harper et al, 2016 ; Loffredo et al, 2013 ; Walker et al, 2016 ). In particular, Gdf11 has been shown to have positive, negative, or neutral effects on muscle growth and mass ( Egerman et al, 2015 ; Egerman and Glass, 2019 ; Honda et al, 2022 ; Rodgers and Eldridge, 2015 ; Sinha et al, 2014 ), indicating that further careful studies with greater scientific rigor and mechanistic approaches are required to elucidate the exact roles of Gdf11 in muscle regeneration and function. Cd24a (also known as Cd24), a small glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein, was initially identified as the first natural ligand of Siglec-G/10 ( Chen et al, 2009 ).…”