Dystrophin is a possible end-target of ischemic preconditioning against cardiomyocyte oncosis during the early phase of reperfusion.

Objective: Dystrophin is a sarcolemmal membrane protein that prevents the myocyte from oncosis induced by physical stress. Because ischemic preconditioning (IPC) protects mitochondria and prevents oncosis during reperfusion, we hypothesized that dystrophin is an end-target of IPC distal to mitochondrial protection.

Methods And Results: Isolated rat hearts were subjected to 30 min ischemia followed by reperfusion. IPC was introduced by 3 cycles of 5 min ischemia and 5 min reperfusion. The loss of sarcolemmal dystrophin and myocardial ATP during ischemia was comparable between the control and the IPC heart. Similar changes in sarcolemmal dystrophin and myocardial ATP were observed when the heart was treated with 2,4-dinitrophenol (DNP), an uncoupler of mitochondrial respiration, or oligomycin, an inhibitor of mitochondrial F1F0-ATPase. However, the IPC heart increased sarcolemmal dystrophin during reperfusion associated with an increase in tetramethylrhodamine ethylester (TMRE) uptake, an indicator of mitochondrial membrane potential (DeltaPsim), and myocardial ATP and inhibited myocyte oncosis. The increase in myocardial ATP and relocalization of dystrophin to the sarcolemma mediated by IPC was inhibited by treatment with DNP or oligomycin during reperfusion. In vitro experiments demonstrated that mitochondria isolated from the ischemic IPC heart increased ATP generation and facilitated relocalization of dystrophin from the insoluble to the soluble fractions in a manner sensitive to DNP and oligomycin.

Conclusions: These results suggest that enhanced relocalization of dystrophin to the sarcolemma during reperfusion may be a mechanistic link between IPC-mediated improvement of mitochondrial function and its protection against oncosis during the early phase of reperfusion.