Myoglobin: safeguard of myocardial oxygen supply during systolic compression?

Myoglobin (Mb) belongs to the family of vertebrate oxygen-binding haem proteins and is predominantly expressed in cardiac and red skeletal muscles that rely on aerobic metabolism to perform sustained work. Additional members of this protein family are of course haemoglobin, the red dye of blood, and the more recently discovered proteins neuroglobin and cytoglobin. Owing to the notoriously low solubility of oxygen in aqueous solutions, haem proteins such as haemoglobin and Mb substantially enhance the total oxygen content in blood and muscle, respectively, and therefore represent important oxygen stores. Mb is expressed at high concentrations in the heart ( 200 mM), and therefore Mb is thought to buffer short phases of ischaemia by release of oxygen when capillary oxygen supply is limited. Another function of Mb, termed ‘facilitated oxygen diffusion’, postulates that besides a flux of physically dissolved oxygen a flux of Mb-bound oxygen may exist. According to this model, oxygen is picked up by Mb at the plasma membrane and is transported to the mitochondria, where it is released and fed into the respiratory chain. In principle, both of these oxygen-related functions of Mb could be relevant because the oxygen partial pressure for half saturation of Mb (P50O2 1⁄4 2.8 mmHg) is far below that of P50O2 for haemoglobin (P50O2 1⁄4 26 mmHg), allowing the transfer of oxygen from the capillary to Mb. However, according to Fick’s law of diffusion, a net oxygen flux contributed by a Mb-mediated facilitated oxygen diffusion requires at first a gradient along which oxygen-loaded Mb may travel. Moreover, a sufficiently high diffusion coefficient (DMb) of the Mb:O2 complex is required to allow a sufficiently rapid migration. Despite of more than 50 years of intensive research, the crucial questions, i.e. under which conditions myocardial PO2 drops to such low levels that Mb releases O2 and also the value of DMb, are still under controversial debate. Therefore, it remains elusive to what extent Mb contributes to myocardial oxygen supply. Endeward et al. have used model calculations based on the Krogh cylinder model to investigate the possible contribution of Mb to cardiac oxygen supply during systole and diastole in a maximally working human heart. In an earlier work, this group has extensively investigated the diffusivity of Mb in striated muscle cells. This value is three to four times lower than others that have been determined, e.g. in concentrated protein solutions, and therefore appears to represent a valid approximation to the in vivo situation. On the basis of their own value for DMb and on measured parameters of coronary flow and oxygen consumption of a maximally working human heart, the calculations of Endeward et al. resulted in clear differences of myoglobin’s contribution to myocardial oxygen supply during systole and diastole, respectively. During diastole, cardiac oxygen supply matches oxygen demand to a large extent and, consequently, myoglobin’s contribution to oxygen supply is only minimal. However, cardiac flow is phasically arrested due to systolic compression, and therefore the authors calculated gradients for PO2 and Mb O2 saturation along the Krogh cylinder that develop during a 150 ms systolic phase. Setting either the diffusion coefficient DMb or Mb concentration to 0, the authors were able to estimate the relative contribution of facilitated O2 diffusion and of oxygen storage functions to total cardiac oxygen supply. They found that Mb contributes substantially to systolic oxygen supply of the heart, both via oxygen storage as well as by facilitated diffusion. Taken together, both functions of Mb are sufficient to maximally bridge one-third of the systolic phase, demonstrating that other sources of oxygen, e.g. haemoglobin-bound O2 in the capillaries, appear to play a larger role than Mb under these conditions. In addition to the calculation of myoglobin contribution to systolic oxygen supply, Endeward et al. also addressed the question to what extent critical factors such as haematocrit, coronary flow, and capillary density, all of which determine cardiac oxygen supply, must be altered in order to compensate for a loss of Mb. These analyses show that minor elevations of these factors are sufficient to compensate for the loss of Mb. In this context, it is interesting to note that Mb knockout mice make use of a combination of all of these mechanisms to adapt to the loss of Mb. What are the implications of these model calculations? This paper predicts a specific role of Mb to ensure oxygen supply during systolic compression with anoxic zones containing highly desaturated Mb, which will form around the venous end of capillaries under high