Myocardial target Role of target Direction of exercise-induced change* Direction of doxorubicin-induced change* Evidence of exercise prevention of doxorubicin-induced change Mechanisms with evidence for their role in exercise prevention Antioxidant to oxidative stress ratio Prevention of oxidative damage ↑ [15 ] ↓ [13 ] ✓ [17 –21 , 52 ] × [23 ] Expression of myosin heavy chain isoform in rodents Motor protein required for muscular contraction; in a healthy rodent heart there is a much higher concentration of the isoform ↑ [154 ] ↓ [155 ] ✓ [28 , 35 –37 ] × [23 ] Caspase 3 and 9 activity Markers for apoptotic signaling ↓ [156 ] ↑ [14 ] ✓ [18 , 23 , 24 , 26 ] HSP 60 expression Controls protein folding and unfolding in response to stress ↑ [18 ] ↑↑ [19 ] ✓ [17 , 19 ] Mitochondrial permeability transition pore opening Regulation of calcium handling and apoptosis ↓ [157 ] ↑ [158 ] ✓ [26 ] Ubiquitin-proteasome activation Maintains protein function and quality control ↓ [159 ] ↑ [160 ] ✓ [24 ] Endothelial progenitor cell level Physiologic and pathologic vessel formation ↑ [54 ] ↓ [161 ] ✓ [55 ] HSP72 expression Controls protein folding and unfolding in response to stress ↑ [18 , 162 ] = [163 ] ✓ [23 ] × [24 , 40 ] SERCA2a expression Calcium recycling from the cytosol into the sarcoplasmic reticulum ↑ [164 ] ↓ [165 ] ✓ [166 ] × [28 , 29 ] Mechanisms with evidence against their role in exercise prevention HSP 70 expression Controls protein folding and unfolding in response to stress ↑ [167 ] ↓ [168 ] × [19 ] AMPK activation Senses and regulates energy homeostasis ↑ [169 ] ↓ [170 ] × [166 ] Cardiac progenitor cell level/heart mass Physiological turnover of cardiomyocytes ↑ [171 ] ↓ [172 ] × [29 ] Expression of PGC-1 Transcription coactivator that regulates mitochondrial biogenesis and angiogenesis = [32 , 33 ] ↓ [173 ] × [22 , 34 ] Potential mechanisms for exercise prevention lacking investigation Neuregulin-1/ErbB4 signalling Cardiac cell survival growth factor ↑ [60 ] ↓ [174 ] Expression of GATA-4 Transcription factor involved in cardiac survival, hypertrophic growth of the heart ↑ [58 ] ↓ [175 ]