Mitochondrial Permeability Transitionin Aging Muscle

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Project Summary/Abstract Mitochondrial permeability transition (MPT) involves the formation of a non-specific pore across the mitochondrial inner membrane that allows the passage of pro-apoptotic proteins and induces a large burst in reactive oxygen species (ROS). Whilst the pathological role of MPT in ischemia-reperfusion injury, cardiac aging, muscular dystrophy and neurodegeneration is well-established, the role of MPT in aging skeletal muscle has not been resolved. Our preliminary data in human and rodent muscle cell cultures identify MPT as a novel mechanism of muscle atrophy that can be blocked by interfering with proteins that regulate MPT, knocking down caspase 3, or by quenching mitochondrial ROS. Furthermore, we show that mitochondria have a lower threshold for inducing MPT in aging muscle, that there is an increased occurrence of MPT in aging human skeletal muscle, and that it only occurs in muscles that atrophy with aging, Finally, we also show in aged muscles that muscle fibers with mitochondria undergoing MPT are severely atrophied relative to normal muscle fibers and that they exhibit features suggesting they are denervated. On this basis, the first goal of this project is to address the fundamental mechanisms linking MPT to muscle atrophy using cell culture models. Secondly, using rat models we will manipulate the Ca2+ threshold for MPT to test the necessity and sufficiency of MPT for generating aging muscle phenotypes. Finally, we will leverage the powerful clinical dataset, deep muscle phenotyping, and availability of muscle histology blocks from the Study of Muscle Mobility and Aging (SOMMA) that will study 875 elderly men and women (³70 y), to establish the translational relevance of MPT for important clinical outcomes in elderly humans. By doing so, our studies will lay the foundation necessary to judge the merits of developing novel therapeutic approaches to prevent sensitization of mitochondria to MPT as a means of preserving muscle mass and mobility in advanced age.