ANT-Dependent MPTP Contributes To Necrotic Myofiber Death In Muscular Dystrophy

The Mitochondrial Permeability Transition Pore (MPTP) is a critical cell death mechanism that contributes to ischemia reperfusion injury in the heart and several degenerative diseases, including Muscular Dystrophy (MD). MD is a family of genetic disorders characterized by progressive muscle wasting, loss of muscle function, and premature death. We have recently demonstrated that the MPTP has two defined genetic components: one consisting of adenosine nucleotide translocase (ANT) family of proteins and a second, unidentified pore that requires the protein cyclophilin D (CypD) to activate. In this study we used MD as a model to test whether this new MPTP model could be applied to a physiological context of necrotic cell death in vivo . We observed that genetic deletion of ANT1 or CypD substantially reduced MD pathology in skeletal muscle, with reduced measures of muscle necrotic cell death, and improved muscle function compared to MD control animals. However, both ANT1KO and CypDKO MD mice still displayed elevated rates of cell death and MD pathology compared to healthy wildtype animals. MD mice lacking both ANT1 and CypD (ANT1KO-CypDKO) virtually eliminated features of skeletal muscle pathology in MD. We observed a near complete loss of MD histopathology, undetectable levels of tissue necrosis, and muscle function that was improved to non-MD levels in ANT1KO-CypDKO MD mice. This study demonstrates that inhibiting both the ANT-dependent and CypD-dependent components of MPTP together can prevent necrotic cell death in an in vivo model. This study also suggests that a therapy that inhibits both MPTP-components can effectively treat MD and may potentially reduce cardiac ischemia reperfusion injury.