The role of HIF1α and HIF2α in muscle development and satellite cell function
Hypoxia inducible factors (HIFs) are central mediators of cellular responses to fluctuations of oxygen, an environmental regulator of stem cell activity. Muscle satellite cells are myogenic stem cells whose quiescence, activation, self-renewal and differentiation are influenced by microenvironment oxygen levels. However, the in vivo roles of HIFs in quiescent satellite cells and activated satellite cells (myoblasts) are poorly understood. Expression analyses indicate that HIF1α and HIF2α are preferentially expressed in pre- and post-differentiation myoblasts, respectively. Interestingly, double knockout of HIF1α and HIF2α (HIF1α/2α dKO) in embryonic myoblasts results in apparently normal muscle development and growth. However, HIF1α/2α dKO in postnatal satellite cells impairs injury-induced muscle repair, accompanied by a reduced number of myoblasts during regeneration. Analysis of satellite cell dynamics on myofibers confirms that HIF1α/2α dKO myoblasts exhibit reduced self-renewal but more pronounced myogenic differentiation under hypoxia conditions. Mechanistically, HIF1α/2α dKO blocks hypoxia-induced activation of Notch signaling, a key determinant of satellite cell self-renewal. Constitutive activation of Notch signaling can rescue HIF1α/2α dKO induced inhibition of satellite cell self-renewal. Together, HIF1α and HIF2α are dispensable for muscle stem cell function under normoxia, but are required for maintaining satellite cell self-renewal under hypoxic environment.
Kuang, Purdue University.
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