Keeping the heart in balance: the functional interactions of myoglobin with nitrogen oxides

SUMMARY Myoglobin (Mb) is an important intracellular oxygen-binding hemoprotein found in the cytoplasm of skeletal and cardiac muscle tissue playing a well-known role in O2 storage and delivery. Within the last decade the knowledge about Mb's function has been considerably extended by the generation of myoglobin-deficient (myo−/−) mice, which for the first time enabled the analysis of Mb's role in physiology without pharmacological intervention. Utilizing the myo−/− mice, it has been demonstrated that beyond its function in O2 supply Mb substantially contributes to nitric oxide (NO) homeostasis in the heart. By a dynamic cycle, in which a decrease in tissue O2 tension drives the conversion of Mb from being a NO scavenger under normoxia to a NO producer during hypoxia, mitochondrial respiration is reversibly adapted to the intracellular O2 tension. Therefore, Mb may act as an important O2 sensor through which NO can regulate muscle energetics and function. As Mb is widespread throughout the fauna, the diverse oxygen-dependent interactions between Mb and nitrogen oxides may not only be of relevance for mammals but also for other vertebrates as evidenced by comparable phenotypes of ‘artificial’ (myo−/− mice) and ‘natural’ Mb knockouts (icefish and amphibians). In conclusion, it seems likely that Mb's multifunctional properties create an environment characterized by a tightly adapted aerobic mitochondrial respiration and low levels of free radicals, and thus serve an essential and beneficial role within the myocardium, which appears to be functionally important over a wide range of species.