Functional and molecular adaptations in skeletal muscle of myoglobin-mutant mice

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.