Lack of dystrophin is associated with altered integration of the mitochondria and ATPases in slow-twitch muscle cells of MDX mice

The potential role of dystrophin-mediated control of systems integrating mi tochondria with ATPases was assessed in muscle cells. Mitochondrial distrib ution and function in skinned cardiac and skeletal muscle fibers from dystr ophin-deficient (MDX) and wild-type mice were compared. Laser confocal micr oscopy revealed disorganized mitochondrial arrays in m. gastrocnemius in MD X mice, whereas the other muscles appeared normal in this group. Irrespecti ve of muscle type, the absence of dystrophin had no effect on the maximal c apacity of oxidative phosphorylation, nor on coupling between oxidation and phosphorylation. However, in the myocardium and m. soleus, the coupling of mitochondrial creatine kinase to adenine nucleotide translocase was attenu ated as evidenced by the decreased effect of creatine on the K-m for ADP in the reactions of oxidative phosphorylation. In m. soleus, a low K-m, for A DP compared to the wild-type counterpart was found, which implies increased permeability for that nucleotide across the mitochondrial outer membrane. In normal cardiac fibers 35% of the ADP flux generated by ATPases was not a ccessible to the external pyruvate kinase-phosphoenolpyruvate system, which suggests the compartmentalized (direct) channeling of that fraction of ADP to mitochondria. Compared to control, the direct ADP transfer was increase d in MDX ventricles. In conclusion. our data indicate that in slow-twitch m uscle cells, the absence of dystrophin is associated with the rearrangement of the intracellular energy and feedback signal transfer systems between m itochondria and ATPases. As the mechanisms mediated by creatine kinases bec ome ineffective, the role of diffusion of adenine nucleotides increases due to the higher permeability of the mitochondrial outer membrane for ADP and enhanced compartmentalization of ADP flux. (C) 2001 Elsevier Science B.V. All rights reserved.