Does hypoxic response enhance overload‐induced muscle hypertrophy ?

We recently established a conditional knockout mouse which exhibits hypoxic response under normoxia. Prolyl hydroxylase domain 2 (PHD2), an enzyme responsible for oxygen dependent hydroxylation of hypoxia inducible factor (HIF), turns HIF susceptible to ubiquitination and subsequent degradation by the proteasome. We previously examined the effect on endurance capacity of PHD2 conditional knockout mice (cKO). A 4‐week training effect on endurance time was more than 1.6 times enhanced in the PHD2 knockout mice (A Nunomiya, et al., Acta Physiol, 2016). Blood flow restriction during strength training are known to facilitate muscle hypertrophy. How hypoxic response is involved in the process of muscle hypertrophy is yet to be clarified. Thus, we hypothesized that overload induced muscle hypertrophy may be enhanced in the PHD2 knockout mice. METHODS We used tamoxifen driven PHD2 cKO mice. After intraperitoneal administration of tamoxifen for 1 week, the cooperative muscles (gastrocnemius and soleus) for the plantaris muscle of the right leg were excised for overloading. Seven days later, we examined the weight, size, fiber‐type composition of the plantar muscles as well as the protein synthesis pathway such as the activation of the mTOR pathway and blood composition such as red blood cell count, VEGF (Vascular endothelial growth factor, EPO (Erythropoietin)). RESULTS Our results show that overloading induced plantaris muscle hypertrophy as compare to the control leg plantaris muscle. The hypertrophy was remarkably enhanced in the PHD2cKO(32% in control vs 83% in PHD2 cKO) . CONCLUSIONS Hypoxic response mediated by HIF pathway enhanced overload‐induced muscle hypertrophy.