Effects of hypoxia on myogenesis and muscular differentiation

Abstract

Oxygen (O2) is an environmental and developmental regulator during several events such as energy homeostasis, development and process of progenitor cells differentiation. Hypoxia corresponds to a decrease in oxygen partial pressure that leads to adaptive responses of skeletal muscle. Activation, proliferation and differentiation of myogenic precursor cells required for muscle growth seem to be mediated by recruitment of several intracellular pathways including calcineurin, p38–MAPK and Akt/mTOR. To examine the hypoxia-induced alterations in these main intracellular signalling pathways during myogenesis two models were used, myoblasts from the L6 line which differentiate in vitro and the embryonic myogenesis using Xenopus laevis embryos. In culture cells, hypoxia delays myoblast differentiation, affecting both calcineurin and Akt signalling pathways, as well as the mTOR downstream, the translation factor S6. In the embryo, hypoxia exposure causes growth retardation and affects differentiation of the myotome cells. These cell events were correlated to an activation of p38-MAPK and a cytoplasmic accumulation of the 4E-BP1 protein specifically in the axial tissues such as the notochord, somites and floor plate. The data show that the 4E-BP1 is a target of hypoxia that reversibly inhibits the cap-dependent translation of mRNA.