Xk‐related protein 8 regulates myoblast differentiation and survival

• Published in: The FEBS journal 2017-11, Vol.284 (21), p.3575-3588
• Main Authors: Kim, Go‐Woon, Nam, Gi‐Hoon, Kim, In‐San, Park, Seung‐Yoon
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Caspase; Cell death; Cell Differentiation; Cell surface; Cell Survival; Differentiation; Exposure; Humans; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Myoblasts; Myoblasts - cytology; Myoblasts - metabolism; Myogenesis; Myotubes; Phosphatidylserine; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; scramblase; Survival; Xk‐related protein 8
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.14261

Xk‐related protein 8 (Xkr8) is a scramblase and responsible for phosphatidylserine (PS) exposure on the cell surface in a caspase‐dependent manner. Although PS exposure is found to be important for myotube formation during myoblast differentiation, the role of Xkr8 during myogenesis has not been elucidated. Here we show that Xkr8 contributes to myoblast differentiation. Xkr8 overexpression induced the formation of large myotubes during early differentiation, but this phenotype was not related to caspase‐dependent cleavage of Xkr8. Furthermore, forced Xkr8 expression accelerated myoblast differentiation and conferred cell‐death resistance after the induction of differentiation. Consistent with these results, Xkr8‐knocked‐down myoblasts exhibited impaired differentiation and more apoptotic cells during differentiation, implying the involvements of Xkr8 in the survival and proliferation of myoblasts. Taken together, the study shows Xkr8 influences myogenesis by acting as a positive regulator of terminal differentiation and myoblast survival. The translocation of phosphatidylserine (PS) to the outer leaflet of the plasma membrane during myoblast differentiation is important for subsequent myotube formation. Xk‐related protein 8 (Xkr8) promotes PS exposure on apoptotic cells in a caspase‐3‐dependent manner, but whether it possesses the same activity during myogenesis was not known. In‐San Kim, Seung‐Yoon Park and colleagues now report a role for Xkr8 in myoblast differentiation. They found that Xkr8 overexpression increased myotube formation, differentiation rate and survival during the early stages of myoblast differentiation. Intriguingly, this activity was not dependent on prior caspase‐3‐mediated cleavage, suggesting that PS exposure in apoptotic and non‐apoptotic cells might use the same machinery that is regulated by different mechanisms.