Palmitoyl Protein Thioesterase 1 Is Essential for Myogenic Autophagy of C2C12 Skeletal Myoblast

Hyeong Rok Yun; Yong Hwa Jo; Jieun Kim; Ngoc Ngo Yen Nguyen; Yoonhwa Shin; Sung Soo Kim; Tae Gyu Choi

doi:10.3389/fphys.2020.569221

Palmitoyl Protein Thioesterase 1 Is Essential for Myogenic Autophagy of C2C12 Skeletal Myoblast

Front Physiol. 2020 Oct 15:11:569221. doi: 10.3389/fphys.2020.569221. eCollection 2020.

Authors

Hyeong Rok Yun^{1

2}, Yong Hwa Jo^{2

3}, Jieun Kim^{2

3}, Ngoc Ngo Yen Nguyen^{2

3}, Yoonhwa Shin^{1

2}, Sung Soo Kim^{2

3}, Tae Gyu Choi^{2

3}

Affiliations

¹ Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, South Korea.
² Biomedical Science Institute, Kyung Hee University, Seoul, South Korea.
³ Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, South Korea.

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.

Keywords: autophagy; mammalian target of rapamycin complex; mitochondrial reactive oxygen species; muscle differentiation; palmitoyl protein thioesterase 1.