Last Word on Viewpoint: Managing the power grid: how myoglobin can regulate Po₂ and energy distribution in skeletal muscle

Thanks to all of the respondents (see Ref. 1) to this Viewpoint (see Ref. 2). This was a true joy.

Bock and Kruse bring up the effects of beetroot supplements in exercising subjects. I agree that a vascular response seems a more likely mechanism for effects of supplements, because presumably there are sufficient muscle nitrate stores to support endogenous reactions with myoglobin (Mb). An important question is whether, in the absence of supplements, endogenous nitrate secreted from muscle could facilitate reactions with cytoglobin residing in the vascular wall to assist in blood flow regulation.

Several authors point out additional mechanisms that could contribute to regulation of the grid. Chris Donnelly describes how local distributions of glycogen might facilitate metabolism close to the sarcolemma. Alain Riveros-Rivera brings up the effect of temperature on Do₂. Dowd et al. (3) modeled temperature effects and found that they can only account for a small fraction of the change in Do₂, but notably they did not evaluate all factors. Li Zuo describes a role for deoxygenated Mb in ROS production. Interestingly, ROS could also suppress respiration in areas of low Po₂. For example, superoxide reacts rapidly with cytochrome c, interfering with upstream electron flow (6), and local H₂O₂ diminishes CcO activity (5). The proximity of CcO and Mb within the intermembrane space (8) would facilitate these reactions.

Daniel Hirai and colleagues refer to the work of Honig and Gayeski who provided a mechanism for elevations in Do₂ with exercise. They showed a disproportionate reduction in Po₂ just below the sarcolemma, reducing the effective diffusion distance for O₂. Diffusion across this narrow gap comprises the “rate limiting step” in myofiber O₂ flux. O₂ gradients across the rest of the fiber are minimized by Mb’s role in facilitated diffusion. The model proposed here adds to the elegance of Honig and Gayeski’s thesis, because simultaneous and disproportionate increases in V̇o₂ in this region would further reduce Po₂ and drive diffusion. Together, these ideas support Honig and Gayeski’s original concept of the “recruited reserve for O₂ diffusive transport” in exercise.

Dr. Pikanova points out myoglobin-deficient muscles in various species perform well through adaptations in blood flow and fiber type. The interplay between both sets of adaptations and how they evolve together with development, evolution, and hypoxic adaptation is a fascinating direction of research. Recent advances in measuring muscle nitrate/nitrite (7) and broad-band NIRS for CcO redox state described here by Rosenberry could bring us answers to these questions.

If this mechanism is actual physiology and not a pipe dream, consider the implications. Glancy and colleagues (4) have shown that the grid can assemble or disassemble itself to improve function. We have to wonder what the effects of chronic disuse, chronic illness, atrophy, and exercise conditioning are to the integrity of this network and the capacity to consume O₂ effectively. As Wayne Willis points out, the capacity of the cellular gas exchange apparatus has always been greater than the sum of its parts. It will take continued efforts of “mitochondriacs” like Wayne with those working on understanding the natural cellular environment around the mitochondria to move our stubborn brains toward a more complete understanding of this wonderful machine.