Myoglobin is a cytoplasmic hemoprotein that is restricted to cardiomyocytes
and oxidative skeletal myofibers and facilitates oxygen delivery during pe
riods of high metabolic demand. Myoglobin content in skeletal muscle increa
ses in response to hypoxic conditions. However, we previously reported that
myoglobin-null mice are viable and fertile. In the present study, we defin
e important functional, cellular, and molecular compensatory adaptations in
the absence of myoglobin. Mice without myoglobin manifest adaptations in s
keletal muscle that include a fiber type transition (type I to type II in t
he soleus muscle), increased expression of the hypoxia-inducible transcript
ion factors hypoxia-inducible factor (HIF)-1 alpha and HIF-2 (endothelial P
AS domain protein), stress proteins such as heat shock protein 27, and the
angiogenic growth factor vascular endothelial growth factor (soleus muscle)
, as well as increased nitric oxide metabolism (extensor digitorum longus).
The resulting changes in angiogenesis, nitric oxide metabolism, and vasomo
tor regulation are likely to account for preserved exercise capacity of ani
mals lacking myoglobin. These results demonstrate that mammalian organisms
are capable of a broad spectrum of adaptive responses that can compensate f
or a potentially serious defect in cellular oxygen transport.