TY - JOUR
T1 - Increase in HDAC9 suppresses myoblast differentiation via epigenetic regulation of autophagy in hypoxia
AU - Zhang, Zhang
AU - Zhang, Liqiang
AU - Zhou, You
AU - Li, Liya
AU - Zhao, Jiangdong
AU - Qin, Wen
AU - Jin, Zuolin
AU - Liu, Wenjia
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/8/1
Y1 - 2019/8/1
N2 - Extremely reduced oxygen (O2) levels are detrimental to myogenic differentiation and multinucleated myotube formation, and chronic exposure to high-altitude hypoxia has been reported to be an important factor in skeletal muscle atrophy. However, how chronic hypoxia causes muscle dysfunction remains unknown. In the present study, we found that severe hypoxia (1% O2) significantly inhibited the function of C2C12 cells (from a myoblast cell line). Importantly, the impairment was continuously manifested even during culture under normoxic conditions for several passages. Mechanistically, we revealed that histone deacetylases 9 (HDAC9), a member of the histone deacetylase family, was significantly increased in C2C12 cells under hypoxic conditions, thereby inhibiting intracellular autophagy levels by directly binding to the promoter regions of Atg7, Beclin1, and LC3. This phenomenon resulted in the sequential dephosphorylation of GSK3β and inactivation of the canonical Wnt pathway, impairing the function of the C2C12 cells. Taken together, our results suggest that hypoxia-induced myoblast dysfunction is due to aberrant epigenetic regulation of autophagy, and our experimental evidence reveals the possible molecular pathogenesis responsible for some muscle diseases caused by chronic hypoxia and suggests a potential therapeutic option.
AB - Extremely reduced oxygen (O2) levels are detrimental to myogenic differentiation and multinucleated myotube formation, and chronic exposure to high-altitude hypoxia has been reported to be an important factor in skeletal muscle atrophy. However, how chronic hypoxia causes muscle dysfunction remains unknown. In the present study, we found that severe hypoxia (1% O2) significantly inhibited the function of C2C12 cells (from a myoblast cell line). Importantly, the impairment was continuously manifested even during culture under normoxic conditions for several passages. Mechanistically, we revealed that histone deacetylases 9 (HDAC9), a member of the histone deacetylase family, was significantly increased in C2C12 cells under hypoxic conditions, thereby inhibiting intracellular autophagy levels by directly binding to the promoter regions of Atg7, Beclin1, and LC3. This phenomenon resulted in the sequential dephosphorylation of GSK3β and inactivation of the canonical Wnt pathway, impairing the function of the C2C12 cells. Taken together, our results suggest that hypoxia-induced myoblast dysfunction is due to aberrant epigenetic regulation of autophagy, and our experimental evidence reveals the possible molecular pathogenesis responsible for some muscle diseases caused by chronic hypoxia and suggests a potential therapeutic option.
UR - https://www.scopus.com/pages/publications/85069486778
U2 - 10.1038/s41419-019-1763-2
DO - 10.1038/s41419-019-1763-2
M3 - 文章
C2 - 31320610
AN - SCOPUS:85069486778
SN - 2041-4889
VL - 10
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 8
M1 - 552
ER -
