By Bethany Veo, PhD
Our muscle cells develop from myogenic stem cells or satellite cells which have the capacity to grow, self-renew, differentiate, and regenerate under the influence of changing oxygen levels sensed from the microenvironment. Hypoxia-inducible factors HIF-1 alpha and HIF-2 alpha are transcription factors that respond to low oxygen levels, activating the expression of target genes. The current understanding of the role that HIF-1 alpha and HIF-2 alpha play in muscle development is contradictory. Case in point, upregulation and downregulation of HIF-1 alpha inhibit myoblast differentiation depending on the oxygen level in vitro.
Transgenic models including mice lacking HIF-2 alpha exhibit early embryonic arrest and HIF-1 alpha knockouts are lethal. Whereas HIF-1 alpha knockouts generated with a different Cre-recombinase survive and show normal skeletal muscle development. Clearly, variations in cellular conditions and specificity of genetic knockout affect the conclusions made regarding the function of either HIF-1 alpha or HIF-2 alpha in muscle cell development. To resolve this ambiguity researchers from Purdue University recently uncovered the dual role of HIF-1 alpha and HIF-2 alpha in regulating myogenic stem cell regeneration under hypoxic versus normal conditions in vivo using two mouse models.
First, to understand whether HIF-1 alpha and HIF-2 alpha fulfill repetitive roles in muscle development both genes were knocked out in muscle cells only, using the MyoD Cre-recombinase driver, which is activated in early myoblasts. The double knockout mice displayed normal muscle development compared with the control mice. In fact, no difference was displayed in the number of myoblasts or in the number of mature myofibers. These results suggested that under normoxic conditions muscle development occurs independently of HIF-1 alpha or HIF-2 alpha.
In a second knockout mouse, the authors used the tamoxifen inducible Pax7 Cre-recombinase to knockout HIF-1 alpha and HIF-2 alpha in satellite cells to understand their role in muscle cell regeneration. Upon induced ischemic injury, the double knockout mice showed a reduction in the ability to regenerate myofibers compared with the controls. Furthermore, during hypoxic conditions satellite cells from the double knockout mice showed reduced self-renewal abilities and enhancement of differentiation without enhanced proliferation. These results suggested that HIF-1 alpha and HIF-2 alpha induce self-renewal of satellite cells under hypoxic conditions.
Lastly, using the Pax7cre double knockout mouse, the authors explored the molecular mechanism of self-renewal induction by HIFs during hypoxic conditions. Coincidentally, Notch signaling, a major network facilitating developmental organization and stem cell fate, is activated by hypoxic conditions. To identify if Notch was activated by HIF-1 alpha and HIF-2 alpha under hypoxia, the Notch1 intercellular domain was examined as well as the downstream targets Hes and Hey. Compared with controls, the induction of hypoxia failed to activate Notch in cells without HIF-1 alpha or HIF-2 alpha. Correspondingly, Notch activation in the HIF-1 alpha and HIF-2 alpha double knockout induced myoblast self-renewal and showed similar response to controls, effectively rescuing the defects.
Thus, the results of this study indicate that HIF-1 alpha and HIF-2 alpha respond to hypoxic conditions in myoblasts by inducing self-renewal, and that loss of HIF-1 alpha and HIF-2 alpha in satellite cells delays muscle regeneration. The implications for this research apply to diseases in which muscle atrophy and degeneration are prominent. These findings also have significant implications for strategies aiming at enhancing muscle cell recovery from acute injury.
Yang, X., Yang, S., Wang, C., Kuang, S. The hypoxia-inducible factors HIF-1 ALPHA and HIF-2 alpha are dispensable for embryonic muscle development but essential for postnatal muscle regeneration.
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