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 ( ${\dot{V}}_{O_2\max }$ ) and exercise performance in myoglobin knockout mice (Mb^-/- ) when compared to control mice (Mb^+/+ ). Furthermore, we also studied NO^• bioavailability, assessed as nitrite (NO₂ ^- ) and nitrate (NO₃ ^- ) 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). ${\dot{V}}_{O_2\max }$ 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 NO₂ ^- levels at rest. During exercise NO₂ ^- increased significantly in the heart and locomotory muscles of Mb^-/- and Mb^+/+ mice, whereas no significant changes in NO₂ ^- were found in plasma. Our study showed that, contrary to recent suggestions, Mb deficiency significantly impairs ${\dot{V}}_{O_2\max }$ and maximal running performance in mice. KEY POINTS: Myoglobin knockout mice (Mb^-/- ) possess lower maximal oxygen uptake ( ${\dot{V}}_{O_2\max }$ ) 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 NO₂ ^- changes in plasma, heart and locomotory muscles. The present study demonstrates that myoglobin is of vital importance for ${\dot{V}}_{O_2\max }$ 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.