Myoglobin is an
oxygen storage molecule that is selectively expressed in cardiac and slow-twitch skeletal muscles that have a high
oxygen demand. Numerous studies have implicated
hypoxia in the regulation of
myoglobin expression as an adaptive response to hypoxic stress. However, the details of this relationship remain undefined. In the present study, adult mice exposed to 10%
oxygen for periods up to 3 wk exhibited increased
myoglobin expression only in the working heart, whereas
myoglobin was either diminished or unchanged in skeletal muscle groups. In vitro and in vivo studies revealed that
hypoxia in the presence or absence of exercise-induced stimuli reprograms calcium signaling and modulates
myoglobin gene expression.
Hypoxia alone significantly altered
calcium influx in response to cell depolarization or depletion of endoplasmic reticulum
calcium stores, which inhibited the expression of
myoglobin. In contrast, our whole animal and transcriptional studies indicate that
hypoxia in combination with exercise enhanced the release of
calcium from the sarcoplasmic reticulum via the
ryanodine receptors triggered by
caffeine, which increased the translocation of nuclear factor of activated T-cells into the nucleus to transcriptionally activate
myoglobin expression. The present study unveils a previously unrecognized mechanism where the
hypoxia-mediated regulation of
calcium transients from different intracellular pools modulates
myoglobin gene expression. In addition, we observed that changes in
myoglobin expression, in response to
hypoxia, are not dependent on
hypoxia-inducible factor-1 or changes in skeletal muscle fiber type. These studies enhance our understanding of
hypoxia-mediated gene regulation and will have broad applications for the treatment of myopathic diseases.