Abstract
Skeletal muscle differentiation is an essential process for the maintenance of muscle development and homeostasis. Reactive oxygen species (ROS) are critical signaling molecules involved in muscle differentiation. Palmitoyl protein thioesterase 1 (PPT1), a lysosomal enzyme, is involved in removing thioester-linked fatty acid groups from modified cysteine residues in proteins. However, the role of PPT1 in muscle differentiation remains to be elucidated. Here, we found that PPT1 plays a critical role in the differentiation of C2C12 skeletal myoblasts. The expression of PPT1 gradually increased in response to mitochondrial ROS (mtROS) during muscle differentiation, which was attenuated by treatment with antioxidants. Moreover, we revealed that PPT1 transactivation occurs through nuclear factor erythroid 2-regulated factor 2 (Nrf2) binding the antioxidant response element (ARE) in its promoter region. Knockdown of PPT1 with specific small interference RNA (siRNA) disrupted lysosomal function by increasing its pH. Subsequently, it caused excessive accumulation of autophagy flux, thereby impairing muscle fiber formation. In conclusion, we suggest that PPT1 is factor a responsible for myogenic autophagy in differentiating C2C12 myoblasts.
Highlights
Skeletal muscle differentiation is a highly coordinated multistep process, which generates myotubes
To investigate the role of Palmitoyl protein thioesterase 1 (PPT1) during muscle differentiation, we examined the morphological changes in C2C12 cells
We found that PPT1 is interrelated with lysosomal function
Summary
Skeletal muscle differentiation is a highly coordinated multistep process, which generates myotubes. Myogenic differentiation requires the expression of a group of basic helix-loop-helix muscle regulatory transcription factors, such as muscle regulatory factors (MRFs), Myf, MyoD, myogenin, and MRF4 (Molkentin and Olson, 1996; Arnold and Winter, 1998). Palmitoyl protein thioesterase 1 (PPT1) is a lysosomal hydrolase that catalyzes the cleavage of thioester linkages in palmitoylated peptides or proteins, which facilitates the degradation of these polypeptides (Camp and Hofmann, 1993; Zeidman et al, 2009). Palmitoylation is one of the most important post-transcriptional protein modifications, which is involved in PPT1 in Myoblast Differentiation subcellular membrane localization of the substrates and proteinprotein interactions (Aicart-Ramos et al, 2011; Zhang and Hang, 2017). The role of PPT1, distinctly from other acyl-protein thioesterases, is considered only in the lysosomal degradation of the substrates (Won et al, 2018)
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