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Mol Cell Biol. 2018 Nov 28;38(24). pii: e00211-18. doi: 10.1128/MCB.00211-18. Print 2018 Dec 15.

Hsp70 Interacts with Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 To Regulate p38MAPK Stability and Myoblast Differentiation during Skeletal Muscle Regeneration.

Fan W#1,2,3, Gao XK#1,2,3, Rao XS#1,2,3, Shi YP1,2,3, Liu XC1,2,3, Wang FY4, Liu YF1,2,3, Cong XX1,2,3, He MY1,2,3, Xu SB1,2,3, Shen WL1,2,3, Shen Y1,2, Yan SG1,2, Luo Y1,2, Low BC5, Ouyang H3,6, Bao Z7, Zheng LL8,2,3,6, Zhou YT8,2,3,6.

Author information

1
Department of Biochemistry and Molecular Biology, Zhejiang University School of Medicine, Hangzhou, China.
2
Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
3
Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China.
4
Department of Pathology, Hospital of Pingdingshan Coal Industry Group, Pingdingshan, China.
5
Mechanobiology Institute, Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
6
China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China.
7
Department of Respiratory Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
8
Department of Biochemistry and Molecular Biology, Zhejiang University School of Medicine, Hangzhou, China zhengliling@zju.edu.cn zhouyt@zju.edu.cn.
#
Contributed equally

Abstract

The regenerative process of injured muscle is dependent on the fusion and differentiation of myoblasts derived from muscle stem cells. Hsp70 is important for maintaining skeletal muscle homeostasis and regeneration, but the precise cellular mechanism remains elusive. In this study, we found that Hsp70 was upregulated during myoblast differentiation. Depletion or inhibition of Hsp70/Hsc70 impaired myoblast differentiation. Importantly, overexpression of p38 mitogen-activated protein kinase α (p38MAPKα) but not AKT1 rescued the impairment of myogenic differentiation in Hsp70- or Hsc70-depleted myoblasts. Moreover, Hsp70 interacted with MK2, a substrate of p38MAPK, to regulate the stability of p38MAPK. Knockdown of Hsp70 also led to downregulation of both MK2 and p38MAPK in intact muscles and during cardiotoxin-induced muscle regeneration. Hsp70 bound MK2 to regulate MK2-p38MAPK interaction in myoblasts. We subsequently identified the essential regions required for Hsp70-MK2 interaction. Functional analyses showed that MK2 is essential for both myoblast differentiation and skeletal muscle regeneration. Taken together, our findings reveal a novel role of Hsp70 in regulating myoblast differentiation by interacting with MK2 to stabilize p38MAPK.

KEYWORDS:

Hsp70/Hsc70; MAPKAPK2; muscle regeneration; myoblast differentiation; myogenesis; p38MAPK

PMID:
30275345
PMCID:
PMC6275188
[Available on 2019-05-28]
DOI:
10.1128/MCB.00211-18

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