Myoglobin knockout (myo-/-) mice reveal several adaptive mechanisms which compensate the loss of the oxygen storage and transport functions of myoglobin. We investigated to what extent myo-/- hearts might adapt to cardiac stress. Therefore, we induced heart failure by chronic isoproterenol application in WT and myo- /- mice. After two weeks, the ISO-induced hypertrophy was not different between WT and myo-/- mice (heart weight index, WT: 5.1±0.3, myo-/-: 5.4±0.6 mg/g) but lung edema occurred only in WT mice (wet/dry lung weight ratio, WT:5.1±0.6, myo-/-: 4.5±0.3). Functional analysis in vivo demonstrated LV dilatation only in WT hearts (EDV, WT: 39±5, myo-/-: 25±4ml) indicating that myo-/- hearts tolerated cardiac stress better than WT hearts. To elucidate mechanisms involved we analyzed gene expression profiles on high density oligonucleotide arrays (Operon Vers.4.0. 25000 genes, 38000 transcripts). ISO led to differential expression of 300-400 transcripts in WT and myo-/- hearts. However, only a minor fraction of these genes was commonly induced in WT and myo-/- hearts. These results suggest that myoglobin deficiency primes the heart to activate a specific gene expression program suitable to prevent a major functional depression due to chronic b-adrenergic superstimulation.