Both hypoxia and work are required to enhance expression of myoglobin in skeletal muscle. Focus on “Hypoxia reprograms calcium signaling and regulates myoglobin expression”

Abstract

THE EFFECTS OF HYPOXIA on mammalian heart and muscle have fascinated physiologists for many a day. Myoglobin is expressed adaptively in muscle. In very young animals, and in the absence of muscle work, the myoglobin concentration in muscles remains very small. What factors lead to myoglobin genesis? Millikan (7) assembled a convincing body of observational and experimental evidence that sustained hard work is required for myoglobin expression. In 1962, Reynafarje (8) showed that life at high altitude favors high concentration of myoglobin in skeletal muscles of humans and small mammals. For a long time, the import of Reynafarje's findings was obscured by apparently contradictory studies showing that low oxygen pressure alone is not a sufficient stimulus for myoglobin expression. Now, Kanatous et al. (5), in the article under discussion, resolve this issue by showing that during hypoxia, myoglobin is elevated in the working heart, but not in the relatively idle skeletal musculature, of mice exposed to prolonged hypoxia. They conclude from their studies that hypoxia alone does not stimulate myoglobin expression, but that hypoxia in consort with repetitive contraction, exactly the conditions obtaining in the muscles of people residing at high altitude, does stimulate myoglobin genesis.Reversible oxygenation permits myoglobin to enhance oxygen flux from regions of high myoglobin oxygen saturation to regions of lower saturation in aqueous solution, a phenomenon named facilitated diffusion (12). This has encouraged physiologists to search for a role of intracellular myoglobin in enhancing oxygen supply to the heart and muscle mitochondria of whole animals to enhance oxidative ATP generation during hypoxia.Reversible oxygenation also permits myoglobin to function as an oxygen store, particularly in animals that work in low oxygen environments such as burrowers, animals living at high altitude, and mammals and birds performing prolonged deep sea dives (4, 6). The myoglobin content of muscles of diving animals often exceeds tenfold that apparently optimal (11) to facilitate oxygen diffusion. The myoglobin content of muscles of diving animals (4, 6) often accounts for ϳ50% of total body oxygen stores, and its concentration is directly correlated with dive duration (4). This raises the interesting question of whether the genetic mechanisms responsible for increased myoglobin expression in working muscles (5) are the same as those generating the massive myoglobin stores of diving animals. Adaptations in diving animals differ from those of the hypoxic, exercising mouse model described below. The diving animals display increased capillary density and mitochondrial volume density, adaptations that promote both diffusive and facilitated oxygen transport to the mitochondria and permit maintenance of aerobic lipid metabolism. These changes are coordinated in diving animals by increased hypoxia-inducible factor (HIF) activation. HIF, the hypoxia-inducible gene program, is a transcriptional activator of downstream target genes th...

Regulation of myoglobin expression

“…This data, in conjunction with the our observations that the skeletal muscles of diving mammals in captivity are significantly less red compared with similar muscle groups from free-ranging counterparts (S.B.K., unpublished data), as well as conflicting studies investigating myoglobin expression in response to hypoxia lead to the hypothesis that hypoxic stress in conjunction with contractile work are required for the increase in myoglobin expression in hypoxiaadapted vertebrates. As discussed in an editorial review of our recent manuscript by Dr Beatrice Wittenberg, a similar hypothesis was put forward as early as 1939 by Dr G. A. Millikan (Millikan, 1939;Wittenberg, 2009).…”

Expression patterns and adaptive functional diversity of vertebrate myoglobins

“…Instead, the release of calcium induced by hypoxia in conjunction with work may initiate the signaling pathway finally leading to increased Mb expression [21,32]. Supporting this model for Mb transcriptional regulation, most recent studies agree that Mb expression in mammalian muscle tissue increases upon exposure to hypoxic stress combined with contractile work, as found in heart [32,33] and exercising skeletal muscle [2,[32][33][34][35]. Surprisingly, Mb in certain skeletal muscle groups of mice and humans may be down-regulated if hypoxia-exposure is the sole factor [32,36].…”

Rapid postnatal development of myoglobin from large liver iron stores in hooded seals

“…The Journal of Experimental Biology 216 (10) Age ( findings in other species (Pattengale and Holloszy, 1967;Kanatous et al, 2009;Wittenberg, 2009).…”

“…The seal fetus is repeatedly exposed to hypoxia in utero, when the mother is diving (Elsner et al, 1969;Liggins et al, 1980), and this most likely triggers the expression of HIF-1 and the development of blood O 2 stores before birth. Mb expression, however, has been shown to be regulated by the calcium-calcineurin-NFAT (nuclear factor of activated T-cells) pathway (Bassel-Duby et al, 1993; Kanatous et al, 2009), which in turn is also partly triggered by hypoxia, but apparently only in combination with muscular activity, at least in mice (Kanatous et al, 2009;Wittenberg, 2009). A recent study using cultured myocytes from Weddell seals (Leptonychotes weddellii) showed that control of Mb development in these animals differs somewhat from that outlined above, in that Mb levels were found to increase in response to hypoxia (and also after lipid supplementation), even in the absence of contraction (De Miranda et al, 2012).…”