A globin in every cell?

A crucial requirement of metabolically active aerobic cells is a steady supply of oxygen. The red pigment of vertebrate skeletal muscle, oxygen-binding myoglobin (Mb), serves this function by facilitating the delivery of O2 from the plasma membrane to the energy-producing mitochondria (1). The delivery of O2 from lungs or gills to muscles is also very efficient because of the cooperative loading and unloading of O2 by the hemoglobin of the red cells. Since Ray Lankester’s (2) first identification, vertebrate Mb has been believed to occur solely in cardiac and skeletal muscle. Only one exception was noted: the smooth muscle sphincter cells of the human rectum, since confirmed (3). Mb can act as a store of O2 to help maintain a constant supply of O2 during rapidly fluctuating demands of contraction (4). This helps explain why the concentration of Mb is highest in the skeletal muscles of diving mammals, and why Mb increases in animals, including humans, after chronic muscular activity or hypoxia (4, 5). In human skeletal muscle, Mb in mitochondriarich oxidative myofibers shows elevated synthesis in response to exposure to high altitudes (5) or intense endurance training under reduced oxygen pressures (4–6). Fraser et al. (7) now report, on page 2977 in this issue of PNAS, that the hypoxiatolerant common carp (Cyprinus carpio) has Mb not only in muscle but also in other metabolically active tissues that include liver, brain, and gills. What is Mb doing in these nonmuscle tissues? Fraser et al. (7) have addressed this question by identifying two unique Mbs in carp tissue, Myg-1 and -2. Myg-1 is expressed not only in muscle but also in liver, kidney, and gill tissue. In these tissues, the Myg-1 gene is strongly upregulated in hypoxia. For example, Myg-1 mRNA expression in liver increased 20-fold after 5 days of hypoxia, and the protein increased 2to 3-fold to approximately half the quantity found in skeletal muscle of nondiving mammals (4). In contrast, expression of Myg-2 occurred only in brain tissue, where it was independent of changes in oxygen pressure. This difference in gene control strongly suggests different functions for the two carp Mbs. Robust in vivo induction of Mb genes by chronic hypoxia, regardless of the training status of the animals, was previously observed in zebrafish gills (8) and in striated muscle of mice (9). The master regulator of cellular O2 homeostasis, the hypoxia-inducible transcription factor 1 (HIF-1), has been implicated in the mouse for this transcriptional activation (9). The possibility that HIF-1 might generally be involved in the induction of Mb is supported by two observations. First, stimulation of the HIF-1 pathway in muscle is triggered by exercise with or without hypoxia and