MOLECULAR GENETICS OF MUSCLE SPECIALIZATION: CARDIAC FUNCTION

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Myoglobin, an intracellular hemoprotein expressed in the heart and oxidative skeletal myofibers of vertebrates, binds molecular oxygen and has been proposed to facilitate oxygen transport from erythrocytes to mitochondria, thereby maintaining cellular respiration during periods of high physiological demand. We generated transgenic mice lacking myoglobin by gene knockout technology and breeding the null allele to homozygosity. Heart and soleus muscles from these animals are depigmented, but mice without myoglobin are fertile and exhibit both normal exercise capacity and a normal ventilatory response to hypoxia. These data demonstrate that myoglobin is not essential to meet the metabolic requirements of pregnancy or exercise in a terrestrial mammal, and raise new questions with respect to oxygen transport and metabolic regulation in working muscles. To determine if loss of myoglobin modulates the response to ischemia and reperfusion, we have recently initiated studies of the isolated working mouse heart preparation. Low flow ischemia is induced by markedly reducing aortic perfusion pressure which reduces coronary perfusion pressure. Using 31P NMR, ATP, PCr, Pi and pH are being measured in the working mouse heart before, during and after 30 minutes of ischemia and 60 minutes of recovery with complementary measures of mechanical performance and creatine kinase release. The results from this study are under evaluation. (Service 14) REPORT PERIOD: (09/01/97-08/31/98)