Pharmacological HIF-PH Inhibition Suppresses Myoblast Differentiation Through Continued HIF-1α Stabilization

TL;DR

This study shows that a drug used to treat anemia can block muscle cell development by keeping a specific protein active.

Contribution

The study reveals a new effect of HIF-PH inhibitors on skeletal muscle differentiation through HIF-1α stabilization.

Findings

FG-4592 suppressed myoblast differentiation into myotubes in vitro.

FG-4592 reduced MyoD, myogenin, and MHC expression while increasing myostatin.

In vivo, FG-4592 decreased muscle differentiation markers in gastrocnemius muscle.

Abstract

Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors continually stabilize hypoxia-inducible factor-1α (HIF-1α). These inhibitors are effective in the clinical treatment of renal anemia. However, the effects of continued HIF-1α stabilization on skeletal muscle differentiation remain unclear. This study aimed to investigate the effects of continued HIF-1α stabilization on skeletal muscle differentiation using a HIF-PH inhibitor in both in vitro and in vivo models. We cultured mouse C2C12 myoblasts to differentiate into myotubes with or without FG-4592, a HIF-PH inhibitor. Additionally, we treated nine-week-old male C57BL/6 mice with either FG-4592 or vehicle via intraperitoneal injections three times a week for four weeks. In vitro, FG-4592 treatment stabilized HIF-1α continually. Morphological analysis revealed that 72 h FG-4592 treatment suppressed differentiation of C2C12 myoblasts into myotubes. This treatment decreased the gene and protein expression of MyoD and myogenin, reduced the protein expression of myosin heavy chain (MHC), and increased the gene and protein expression of myostatin. HIF-1α knockdown mitigated the decrease in MHC protein expression induced by FG-4592. In vivo, FG-4592 treatment increased HIF-1α protein expression and decreased MyoD, myogenin, and MHC protein expression in gastrocnemius muscle. These findings suggest that pharmacological HIF-PH inhibition suppresses myoblast differentiation through continued HIF-1α stabilization.

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