Abstract
The role of Notch signaling is widely studied in skeletal muscle regeneration but little is known about its influences on muscle protein synthesis (MPS). The purpose of this study was to investigate whether Notch signaling is involved in the regulation of MPS. C2C12 cells were treated with a γ-secretase inhibitor (GSI), to determine the effect of reduced Notch signaling on MPS and anabolic signaling markers. GSI treatment increased myotube hypertrophy by increasing myonuclear accretion (nuclei/myotube: p = 0.01) and myonuclear domain (myotube area per fusing nuclei: p < 0.001) in differentiating C2C12 cells. GSI treatment also elevated myotube hypertrophy in differentiated C2C12s (area/myotube; p = 0.01). In concert, GSI treatment augmented pmTOR Ser2448 (p = 0.01) and protein synthesis (using SUnSET method) in myotubes (p < 0.001). Examining protein expression upstream of mTOR revealed reductions in PTEN (p = 0.04), with subsequent elevations in pAKT Thr308 (p < 0.001) and pAKT Ser473 (p = 0.05). These findings reveal that GSI treatment elevates myotube hypertrophy through both augmentation of fusion and MPS. This study sheds light on the potential multifaceted roles of Notch within skeletal muscle. Furthermore, we have demonstrated that Notch may modulate the PTEN/AKT/mTOR pathway.
Highlights
Aging and skeletal muscle-associated diseases can lead to significant reductions in skeletal muscle mass, which impedes quality of life and the ability for individuals to perform activities of daily living [1,2,3]
Our findings revealed that Notch may serve as a molecular brake on myotube hypertrophy through regulation of both myonuclear accretion and expansion of myonuclear domain
This study further elucidated the molecular braking effect that Notch signaling has on skeletal muscle
Summary
Aging and skeletal muscle-associated diseases (e.g., diabetes, cancer cachexia) can lead to significant reductions in skeletal muscle mass, which impedes quality of life and the ability for individuals to perform activities of daily living [1,2,3]. The reductions in skeletal muscle mass in these debilitating conditions are partly attributed to dysfunction in myogenesis and muscle protein synthesis (MPS). Notch signaling occurs when one of its transmembrane receptors, Notch, Notch, Notch, or Notch, binds a Notch ligand (Delta-like protein (DLL), DLL3, DLL4, Jagged, and Jagged2), initiating a series of metalloprotease and γ -secretase driven cleavages. In addition to its pivotal roles during development, Notch signaling is crucial for a successful myogenic response following injury [4,5]. Notch signaling may be dysfunctional in aged skeletal muscle, resulting in a weakened myogenic response. Dysfunctional Notch signaling has been identified as a contributor to the development of insulin resistance and cachexic muscle [6,7,8]
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