Myoglobin deficiency impairs maximal oxygen uptake and exercise performance: a lesson from Mb -/- mice.

Myoglobin (Mb) plays an important role at rest and during exercise as a reservoir of oxygen and has been suggested to regulate NO • bioavailability under hypoxic/acidic conditions. However, its ultimate role during exercise is still a subject of debate. We aimed to study the effect of Mb deficiency on maximal oxygen uptake ( V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_2}\max }}$ ) and exercise performance in myoglobin knockout mice (Mb -/- ) when compared to control mice (Mb +/+ ). Furthermore, we also studied NO • bioavailability, assessed as nitrite (NO 2 - ) and nitrate (NO 3 - ) in the heart, locomotory muscle and in plasma, at rest and during exercise at exhaustion both in Mb -/- and in Mb +/+ mice. The mice performed maximal running incremental exercise on a treadmill with whole-body gas exchange measurements. The Mb -/- mice had lower body mass, heart and hind limb muscle mass (P < 0.001). Mb -/- mice had significantly reduced maximal running performance (P < 0.001). V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_2}\max }}$ expressed in ml min -1 in Mb -/ - mice was 37% lower than in Mb +/+ mice (P < 0.001) and 13% lower when expressed in ml min -1  kg body mass -1 (P = 0.001). Additionally, Mb -/- mice had significantly lower plasma, heart and locomotory muscle NO 2 - levels at rest. During exercise NO 2 - increased significantly in the heart and locomotory muscles of Mb -/- and Mb +/+ mice, whereas no significant changes in NO 2 - were found in plasma. Our study showed that, contrary to recent suggestions, Mb deficiency significantly impairs V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_2}\max }}$ and maximal running performance in mice. KEY POINTS: Myoglobin knockout mice (Mb -/- ) possess lower maximal oxygen uptake ( V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_2}\max }}$ ) and poorer maximal running performance than control mice (Mb +/+ ). Respiratory exchange ratio values at high running velocities in Mb -/- mice are higher than in control mice suggesting a shift in substrate utilization towards glucose metabolism in Mb -/- mice at the same running velocities. Lack of myoglobin lowers basal systemic and muscle NO • bioavailability, but does not affect exercise-induced NO 2 - changes in plasma, heart and locomotory muscles. The present study demonstrates that myoglobin is of vital importance for V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_2}\max }}$ and maximal running performance as well as explains why previous studies have failed to prove such a role of myoglobin when using the Mb -/- mouse model.